The c.922A>G (p.Asn308Asp) variant in PTPN11 has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 20979190, and 11704759, 22465605). The variant has co-segregated with disease in more than 7 family members (PP1_Strong; PMID: 11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn308Asp variant may impact the protein (PP3). Additionally, at least 2 functional studies have been concordant in showing that this variant may be deleterious to the protein (PS3; PMID 14974085, 15987685, 19509418, 20308328). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM2, PP1_Strong, PS2_VeryStrong, PS3.
ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
for
Noonan syndrome
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp)
Variation ID: 13326 Accession: VCV000013326.124
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.13 12: 112477719 (GRCh38) [ NCBI UCSC ] 12: 112915523 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 3, 2013 Nov 24, 2024 Apr 3, 2017 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002834.5:c.922A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Asn308Asp missense NM_001330437.2:c.922A>G NP_001317366.1:p.Asn308Asp missense NM_001374625.1:c.919A>G NP_001361554.1:p.Asn307Asp missense NM_080601.3:c.922A>G NP_542168.1:p.Asn308Asp missense NC_000012.12:g.112477719A>G NC_000012.11:g.112915523A>G NG_007459.1:g.63988A>G LRG_614:g.63988A>G LRG_614t1:c.922A>G LRG_614p1:p.Asn308Asp Q06124:p.Asn308Asp - Protein change
- N308D, N307D
- Other names
-
p.N308D:AAT>GAT
NM_002834.4(PTPN11):c.922A>G
- Canonical SPDI
- NC_000012.12:112477718:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PTPN11 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
972 | 984 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (35) |
criteria provided, multiple submitters, no conflicts
|
Oct 10, 2024 | RCV000014254.86 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 26, 2024 | RCV000033516.28 | |
| Pathogenic (16) |
criteria provided, multiple submitters, no conflicts
|
May 12, 2023 | RCV000077863.60 | |
| Pathogenic (3) |
reviewed by expert panel
|
Apr 3, 2017 | RCV000156977.20 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 22, 2021 | RCV000515324.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 1, 2017 | RCV000576594.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2022 | RCV000621227.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 24, 2019 | RCV000999988.15 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 21, 2018 | RCV000850589.16 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 12, 2023 | RCV001253546.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001293867.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 7, 2021 | RCV001813192.11 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 1, 2020 | RCV001270562.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 12, 2023 | RCV003147284.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 1, 2023 | RCV003991568.1 | |
|
PTPN11-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Apr 17, 2024 | RCV004541002.2 |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 03, 2017)
|
reviewed by expert panel
Method: curation
|
Noonan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000616374.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.922A>G (p.Asn308Asp) variant in PTPN11 has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical … (more)
The c.922A>G (p.Asn308Asp) variant in PTPN11 has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 20979190, and 11704759, 22465605). The variant has co-segregated with disease in more than 7 family members (PP1_Strong; PMID: 11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn308Asp variant may impact the protein (PP3). Additionally, at least 2 functional studies have been concordant in showing that this variant may be deleterious to the protein (PS3; PMID 14974085, 15987685, 19509418, 20308328). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM2, PP1_Strong, PS2_VeryStrong, PS3. (less)
|
|
|
Pathogenic
(Oct 26, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
de novo
|
Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000897976.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
Age: 10-19 years
Sex: male
|
|
|
Pathogenic
(Dec 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
LEOPARD syndrome 1
Metachondromatosis Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000992812.1
First in ClinVar: Sep 23, 2019 Last updated: Sep 23, 2019 |
|
|
|
Pathogenic
(Jan 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000206699.4
First in ClinVar: Jan 31, 2015 Last updated: Feb 10, 2020 |
Comment:
The PTPN11 p.Asn308Asp variant (rs28933386, ClinVar variant ID 13326) is frequently found in patients diagnosed with Noonan syndrome (Ezquita 2012, Jongmans 2005, Kosaki 2002, Papadopoulou … (more)
The PTPN11 p.Asn308Asp variant (rs28933386, ClinVar variant ID 13326) is frequently found in patients diagnosed with Noonan syndrome (Ezquita 2012, Jongmans 2005, Kosaki 2002, Papadopoulou 2012, Tafazoli 2018, Tartaglia 2001, Tartaglia 2002, Tartaglia 2006, Ueda 2017, van Nierop 2017, Zenker 2004), and co-segregates with affected individuals (Tartaglia 2002). The variant is located in the phospho-tyrosine phosphatase domain of PTPN11 (Qiu 2014, Tartaglia 2001), and additional missense variants at this residue have also been associated with Noonan syndrome (Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Asn308Asp protein indicates increased catalytic activity (Fragale 2004, Keilhack 2005, Qui 2014, Tartaglia 2006) due to stabilization of the active enzyme (Qiu 2014). This leads to over-activation of phospho-MEK and phospho-ERK signaling (Fragale 2004), consistent with the established disease mechanisms of Noonan syndrome. The p.Asn308Asp variant is therefore classified as pathogenic. References: Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 65(5):447-55. Fragale A et al. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat 2004 23(3):267-77. Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 19(8):870-4. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 280(35):30984-93. Kosaki K et al. PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab. 2002 87(8):3529-33. Papadopoulou A et al. Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. Eur J Pediatr. 2012 171(1):51-8. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 14:10. Tafazoli A et al. Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing. Adv Med Sci. 2018 Mar;63(1):87-93. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 29(4):465-8. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 70(6): 1555-1563. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 78(2): 279-290. Ueda K et al. Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. Am J Med Genet A. 2017 Sep;173(9):2346-2352. van Nierop JWI et al. Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11. Int J Pediatr Otorhinolaryngol. 2017 Jun;97:228-234. Zenker M et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004 144(3):368-74. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426644.1
First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020 |
|
|
|
Pathogenic
(Aug 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
LEOPARD syndrome 1
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001370072.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3.
|
|
|
Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061275.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.922A>G;p.(Asn308Asp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13326; PMID: 11992261; 14974085; 15987685; … (more)
The c.922A>G;p.(Asn308Asp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13326; PMID: 11992261; 14974085; 15987685; 19509418; 20308328; 20979190; 11704759; 22465605) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:14974085, 15987685, 19509418, 20308328) - PS3. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 20979190; 11704759; 22465605) - PS2.The variant is present at low allele frequencies population databases (rs28933386– gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 11992261) - PP1_strong. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
|
|
|
Pathogenic
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
de novo
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002515370.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
LEOPARD syndrome 1
Affected status: yes
Allele origin:
de novo
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002567948.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jul 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580043.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PP1_STR, PM2_SUP, PP2, PP3
|
Number of individuals with the variant: 4
Sex: female
|
|
|
Pathogenic
(Oct 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
LEOPARD syndrome 1
Metachondromatosis Noonan syndrome 1 Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611308.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Mar 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807384.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP1 strong, PP2 supporting, PP3 supporting
Number of individuals with the variant: 1
Clinical Features:
Primary Caesarian section (present) , Abnormal delivery (present) , Caesarian section (present) , Intellectual disability (present) , Maternal hypertension (present) , Anteverted nares (present) , … (more)
Primary Caesarian section (present) , Abnormal delivery (present) , Caesarian section (present) , Intellectual disability (present) , Maternal hypertension (present) , Anteverted nares (present) , Bulbous nose (present) , Depressed nasal bridge (present) , Moderately short stature (present) , Intellectual disability, mild (present) , Proportionate short stature (present) , Smooth philtrum (present) , Short palm (present) , Microtia (present) , Short stature (present) , Thick vermilion border (present) , Microtia, first degree (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(Jun 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
de novo
|
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam
Accession: SCV003934966.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Number of individuals with the variant: 1
Geographic origin: Vietnam
|
|
|
Pathogenic
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
LEOPARD syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835352.2
First in ClinVar: Mar 11, 2023 Last updated: Oct 06, 2023 |
|
|
|
Pathogenic
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Metachondromatosis
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835459.2
First in ClinVar: Mar 11, 2023 Last updated: Oct 06, 2023 |
|
|
|
Pathogenic
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001522578.3
First in ClinVar: Mar 22, 2021 Last updated: Oct 06, 2023 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047634.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The PTPN11 c.922A>G (p.Asn308Asp) variant has been reported to segregate with disease in many families with Noonan syndrome and related conditions (Tartaglia M et al). … (more)
The PTPN11 c.922A>G (p.Asn308Asp) variant has been reported to segregate with disease in many families with Noonan syndrome and related conditions (Tartaglia M et al). Experimental studies have shown that this missense change is located in the conserved protein-tyrosine phosphatase domain of the PTPN11 protein and results in higher levels of activity (Tartaglia M et al). This variant is reported with the allele frequency (0.0012%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar Pathogenic. The amino acid Asn at position 308 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asn308Asp in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Tetraparesis (present) , Headache (present) , Abnormal facial shape (present)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV004099299.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
|
|
|
Pathogenic
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
de novo
|
Department of Pediatrics, The Affiliated Hospital of Qingdao University
Accession: SCV004102641.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Clinical Features:
Chiari I malformation (present) , syringomyelia (present) , short stature (present) , developmental delay (present) , mild intellectual disability (present) , oatrial septal defects (present)
|
|
|
Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: research
|
Male infertility with azoospermia or oligozoospermia due to single gene mutation
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Laan Lab, Human Genetics Research Group, University of Tartu
Accession: SCV004231705.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
Sex: male
|
|
|
Pathogenic
(Jun 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061329.7
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Asn308Asp variant in PTPN11 is an established pathogenic variant for Noonan syndrome and has been reported in approximately 11-20% of individuals with Noonan syndrome … (more)
The p.Asn308Asp variant in PTPN11 is an established pathogenic variant for Noonan syndrome and has been reported in approximately 11-20% of individuals with Noonan syndrome across multiple studies (Tartaglia 2001 PMID: 11704759, Jongmans 2005 PMID: 15723289, Tartaglia 2006 PMID: 16358218, Jongmans 2011 PMID: 21407260, Ezquieta 2012 PMID: 22465605). In addition, de novo occurrences and germline mosaicism have been described (Tartaglia 2001 PMID: 11704759, Elalaoui 2010 PMID: 20979190, Ezquieta 2012 PMID: 22465605). This variant has been identified in 0.001% (3/251440) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreover, this variant has been classified as pathogenic on April 03, 2017 by the ClinGen-approved RASopathy expert panel (SCV000616374.3). In vitro functional studies provide some evidence that this variant impacts protein function (Fragale 2004 PMID: 14974085, Niihori 2005 PMID: 15834506). Additional variants involving this codon (p.Asn308Ser and p.Asn308Thr) have been identified in individuals with Noonan syndrome and are classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based on its frequency in affected individuals and de novo occurrences. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM5_Strong, PS3_Moderate. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
paternal
|
Henan Neurodevelopment Engineering Research Center for Children, Children's Hospital Affiliated to Zhengzhou University
Accession: SCV005374702.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Age: 0-9 years
Sex: female
|
|
|
Pathogenic
(Oct 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557523.3
First in ClinVar: Aug 08, 2022 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene associated with Noonan syndrome are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the protein tyrosine phosphatase domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well established as a pathogenic variant for Noonan syndrome (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jun 03, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown,
de novo
|
UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255510.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Observation 1:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Observation 2:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
|
|
|
Pathogenic
(Nov 10, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000207168.3
First in ClinVar: Feb 06, 2015 Last updated: Apr 09, 2018 |
Number of individuals with the variant: 4
|
|
|
Pathogenic
(Aug 18, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown,
maternal
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000265839.1
First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015 |
Observation 1:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Hypertelorism (present) , Low set ears (present) , Short stature (present) , Broad webbed neck (present) , Developmental delay (present)
Age: 10-19 years
Sex: male
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Congenital pulmonic valve stenosis (present) , Eyelid deformation (present) , Failure to thrive (present)
Age: 0-9 years
Sex: female
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Short stature (present) , Hypertension (present)
Age: 10-19 years
Sex: male
|
|
|
Pathogenic
(Aug 26, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
de novo
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281404.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
|
|
|
Pathogenic
(Jul 11, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000614840.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
|
|
|
Pathogenic
(Aug 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
LEOPARD syndrome 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000678233.1
First in ClinVar: Jan 07, 2018 Last updated: Jan 07, 2018 |
Comment:
PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has … (more)
PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has been identified in >20 probands with Noonan syndrome and segregating with disease in at least 7 affected relatives (Tartaglia 2001 PMID:11704759, Tartaglia 2002 PMID:11992261, Brasil 2010 PMID:21340158, Jongmans 2011 PMID:21407260, Prada 2011 PMID:21567923, Ejarque 2015 PMID:25912702, van Trier 2016 PMID:27521173, van Nierop 2017 PMID:28483241). This variant is present in 3/246202 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28933386). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13326). Evolutionary conservation and computational predictive tools for this variant are unclear. However, functional studies have shown a deleterious effect of this variant on the protein (Fragale 2004 PMID:14974085, Oishi 2006 PMID:16399795, Qiu 2014 PMID:24628801). Of note, at least one other variant at this position (p.Asn308Ser) has been associated with disease at this position, supporting that this region is functionally significant. In summary, this variant is classified as pathogenic (high presence of affected probands, segregation studies, absence from controls, functional studies). (less)
|
|
|
Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782251.1
First in ClinVar: Feb 15, 2018 Last updated: Feb 15, 2018 |
|
|
|
Pathogenic
(Sep 16, 2018)
|
criteria provided, single submitter
Method: research
|
not provided
Affected status: yes
Allele origin:
germline
|
Gharavi Laboratory, Columbia University
Accession: SCV000809183.1
First in ClinVar: Feb 15, 2018 Last updated: Feb 15, 2018 |
|
|
|
Pathogenic
(Jan 11, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232628.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 5
Sex: mixed
|
|
|
Pathogenic
(Nov 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Rasopathy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698085.2
First in ClinVar: Dec 26, 2017 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PTPN11 c.922A>G (p.Asn308Asp) results in a conservative amino acid change located in the PTP type protein phosphatase of the encoded protein sequence. Three … (more)
Variant summary: PTPN11 c.922A>G (p.Asn308Asp) results in a conservative amino acid change located in the PTP type protein phosphatase of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251830 control chromosomes. c.922A>G has been reported in the literature in numerous individuals affected with Noonan Syndrome. These data indicate that the variant is very likely to be associated with disease. Residue 308 is located in the PTP domain and is reported as the most common residue affected in NS patients (N308D and N308S). Functional studies showed that this variant leads to a mild activation of the protein's catalytic activity (about 3-fold higher than WT; Keilhack_2005). 16 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
LEOPARD syndrome 1 Metachondromatosis
Affected status: yes
Allele origin:
germline
|
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV001423673.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
Comment:
[ACMG/AMP/ClinGen RASopathy: PS2_VeryStrong, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental … (more)
[ACMG/AMP/ClinGen RASopathy: PS2_VeryStrong, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2_VeryStrong], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. (less)
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|
|
Pathogenic
(Feb 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
LEOPARD syndrome 1
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429315.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001430036.1
First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020 |
Observation 1:
Clinical Features:
Global developmental delay (present) , Short stature (present) , Leukemia (present)
Sex: female
Tissue: blood
Observation 2:
Clinical Features:
Decreased response to growth hormone stimulation test (present) , Short stature (present)
Sex: male
Tissue: blood
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447054.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present)
Sex: female
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
de novo
|
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf
Accession: SCV001482282.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Clinical Features:
Hypertelorism (present) , Wide nasal base (present) , Deep philtrum (present) , Wide intermamillary distance (present) , Ventricular septal defect (present) , Patent foramen ovale … (more)
Hypertelorism (present) , Wide nasal base (present) , Deep philtrum (present) , Wide intermamillary distance (present) , Ventricular septal defect (present) , Patent foramen ovale (present) , Hearing impairment (present) , Delayed speech and language development (present) (less)
Family history: no
|
|
|
Pathogenic
(Sep 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000057421.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 15, 2018 |
Comment:
N308D is the most common variant causing Noonan syndrome (Tartaglia et al., 2002); Most individuals have mild or no cognitive impairment (Pierpont et al., 2009; … (more)
N308D is the most common variant causing Noonan syndrome (Tartaglia et al., 2002); Most individuals have mild or no cognitive impairment (Pierpont et al., 2009; Tartaglia et al., 2002); Published functional studies indicate altered local hydrogen bond network of the PTPN11 protein and increased basal phosphatase activity compared to wild-type protein (Qiu et al., 2014; Fragale et al., 2004); Classified as pathogenic by the ClinGen RASopathy Expert Panel (ClinVar SCV000616374.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 20308328, 16399795, 26607044, 21567923, 26377682, 27521173, 11704759, 20979190, 30294303, 28991257, 19352411, 21407260, 14974085, 15987685, 19509418, 25912702, 24628801, 11992261, 24803665, 26918529, 23726368, 24072241, 22822385, 19077116, 26785492, 21340158, 28135719, 28957739, 28650561, 28483241, 18253957, 29214238, 30355600, 26645620, 29848529, 30417923, 30050098, 29263817, 30287924, 29907801, 31219622, 31637070, 31560489, 32164556, 32054441, 32935436, 32150461, 32369273, 31216405, 32371413, 32581362, 31589614, 33300679, 33258288) (less)
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|
|
Pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
unknown
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976688.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PS3, PM1, PM5, PP2, PP3, PP4, PP5
|
|
|
Pathogenic
(May 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome and Noonan-related syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060448.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
|
Pathogenic
(Nov 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061706.3
First in ClinVar: Jan 22, 2022 Last updated: Aug 05, 2023 |
Comment:
PS2, PS3, PS4, PP1, PP2, PP3, PM1, PM5
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud
Accession: SCV002098086.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
Clinical Features:
Pulmonic stenosis (present) , auricular septal defect (present) , suspected noonan syndrome. Relative macrocephaly (present) , wide forehead (present) , descending palpebral fissures (present) , … (more)
Pulmonic stenosis (present) , auricular septal defect (present) , suspected noonan syndrome. Relative macrocephaly (present) , wide forehead (present) , descending palpebral fissures (present) , slightly spread ears (present) , fine nose (present) , bulbous tip (present) , short neck without pterygium (present) , pectus excavatum (present) , unilateral cryptorchidism (present) , linear hyperpigmentation on the inner side of the right arm and forearm following the line of blaschko (present) , scoliosis (present) (less)
Sex: male
Tissue: blood
Secondary finding: no
|
|
|
Pathogenic
(Jun 05, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501845.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521166.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013326). The variant has … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013326). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 11704759,20979190,22465605) and co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID:11992261). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:14974085, 15987685, 19509418, 20308328). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.98). Different missense changes at the same codon (p.Asn308Ser, p.Asn308Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013327, VCV000040535). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal nerve conduction velocity (present) , Cardiac arrhythmia (present) , Left ventricular diastolic dysfunction (present)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
LEOPARD syndrome 1
Metachondromatosis Noonan syndrome 1 (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Suma Genomics
Accession: SCV002543808.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
de novo
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559228.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
|
Pathogenic
(Dec 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
de novo
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000778402.2
First in ClinVar: Feb 15, 2018 Last updated: Mar 26, 2023 |
Method: Exome sequencing
|
|
|
Pathogenic
(Nov 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
LEOPARD syndrome 1 Metachondromatosis Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920363.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has … (more)
PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has been identified in >20 probands with Noonan syndrome and segregating with disease in at least 7 affected relatives (Tartaglia 2001 PMID:11704759, Tartaglia 2002 PMID:11992261, Brasil 2010 PMID:21340158, Jongmans 2011 PMID:21407260, Prada 2011 PMID:21567923, Ejarque 2015 PMID:25912702, van Trier 2016 PMID:27521173, van Nierop 2017 PMID:28483241). This variant is present in 3/246202 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28933386). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13326). Evolutionary conservation and computational predictive tools for this variant are unclear. However, functional studies have shown a deleterious effect of this variant on the protein (Fragale 2004 PMID:14974085, Oishi 2006 PMID:16399795, Qiu 2014 PMID:24628801). Of note, at least one other variant at this position (p.Asn308Ser) has been associated with disease at this position, supporting that this region is functionally significant. In summary, this variant is classified as pathogenic (high presence of affected probands, segregation studies, absence from controls, functional studies). (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003924404.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
A Heterozygous Missense variant c.922A>G in Exon 8 of the PTPN11 gene that results in the amino acid substitution p.Asn308Asp was identified. The observed variant … (more)
A Heterozygous Missense variant c.922A>G in Exon 8 of the PTPN11 gene that results in the amino acid substitution p.Asn308Asp was identified. The observed variant has a maximum allele frequency of 0.00001% in gnomAD exomes and novel in genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID:13326]. This variant has previously been reported for Noonan syndrome by Jeevana PA et al., 2020. For these reasons, this variant has been classified as Pathogenic. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
|
|
Pathogenic
(May 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714427.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 03, 2023 |
|
|
|
Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004101294.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The PTPN11 c.922A>G (p.Asn308Asp) missense variant is one of the most common pathogenic variants associated with Noonan syndrome. In most cases, this variant occurs as … (more)
The PTPN11 c.922A>G (p.Asn308Asp) missense variant is one of the most common pathogenic variants associated with Noonan syndrome. In most cases, this variant occurs as the result of a de novo event, but also has been shown to segregate with disease in affected individuals within families (PMID: 11992261; 19352411; 20301303; 20979190; 22465605). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies demonstrate that this variant impacts protein function (PMID: 15987685; 19509418). This variant has been classified as pathogenic in ClinVar by several submitters, including the ClinGen RASopathy Expert Panel. This variant was identified in a de novo state. Based on the available evidence, the c.922A>G (p.Asn308Asp) variant is classified as pathogenic for Noonan syndrome. (less)
|
|
|
Pathogenic
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019553.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000219003.13
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 308 of the PTPN11 protein … (more)
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 308 of the PTPN11 protein (p.Asn308Asp). This variant is present in population databases (rs28933386, gnomAD 0.004%). This missense change has been observed in individual(s) with Noonan syndrome and related conditions (PMID: 11704759, 16358218, 21340158, 21567923; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13326). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16358218, 19509418, 20308328). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Juvenile myelomonocytic leukemia
Noonan syndrome 1 Metachondromatosis LEOPARD syndrome 1
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
de novo
|
Molecular Genetics Lab, CHRU Brest
Accession: SCV004697714.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: research
|
Noonan syndrome 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805488.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Feb 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000736587.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The p.N308D pathogenic mutation (also known as c.922A>G), located in coding exon 8 of the PTPN11 gene, results from an A to G substitution at … (more)
The p.N308D pathogenic mutation (also known as c.922A>G), located in coding exon 8 of the PTPN11 gene, results from an A to G substitution at nucleotide position 922. The asparagine at codon 308 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was first reported in three families and one sporadic proband with Noonan syndrome; however, specific diagnostic criteria were not strictly defined in this study (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8). The Asn308 residue is located in the PTP (protein tyrosine phosphate) domain, and it has been described as a mutational hot spot, with p.N308D referred to as the most common Noonan syndrome mutation accounting for 25% of cases. In the same studies, functional in vitro analyses revealed that this alteration increases protein tyrosine phosphatase activity in the catalytic domain compared to wild type due to gain-of-function effects (Fragale A et al. Hum. Mutat., 2004 Mar;23:267-77; Qiu W et al. BMC Struct. Biol., 2014 Mar;14:10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 26, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
inherited
|
New York Genome Center
Study: PrenatalSEQ
Accession: SCV005044093.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Comment:
The inherited heterozygous c.922A>G, p. (Asn308Asp) in PTPN11 is reported as one of the most common variants and accounts for 25% of Noonan syndrome cases. … (more)
The inherited heterozygous c.922A>G, p. (Asn308Asp) in PTPN11 is reported as one of the most common variants and accounts for 25% of Noonan syndrome cases. This c.922A>G variant has previously been identified in both de novo and inherited occurrences in individuals with Noonan syndrome [PMID:20979190, 22465605, 26645620, 32164556, 34411415, 35440950, 34194850] and found to be co-segregated with disease [PMID: 11992261]. The c.922A>G variant has been classified as Pathogenic for Noonan syndrome by ClinGen RASopathy Variant Curation Expert Panel [ClinVar ID: 13326] and observed in 5 allele (~0.0011% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.922A>G variant in PTPN11 is located in exon 8 of this 16-exon gene and predicted to replace an evolutionarily conserved asparagine amino acid with aspartic acid p. (Asn308Asp) in the protein tyrosine phosphatase (PTP) domain of the encoded protein and has been described as a mutational hot spot [PMID: 32164556,24628801]. In vitro functional studies demonstrated increased phosphatase activity indicating the gain-of-function effects in fibroblast cells carrying c.922A>G variant [PMID: 14974085, 15987685, 19509418, 20308328]. In silico predictions are in favor of damaging effect for p.(Asn308Asp) [(CADD v1.6 = 24.5, REVEL = 0.84)]. Other missense variants affecting the same p.(Asn308) residue have been reported in the literature (p.Asn308Ser) [PMID: 32164556] and ClinVar [ClinVar IDs: 13327] in individuals with Noonan syndrome. Based on available evidence this inherited heterozygous c.922A>G p.(Asn308Asp) in PTPN11 is classified as Pathogenic for Noonan syndrome 1. (less)
Clinical Features:
Fetal cystic hygroma (present)
Age: 20-29 weeks gestation
Secondary finding: no
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Medical University Innsbruck
Accession: SCV005044703.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
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Pathogenic
(May 27, 2022)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197303.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Jun 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004698055.3
First in ClinVar: Mar 10, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PS2_VSTR,PS4,PS3_MOD,PP3
Clinical Features:
Motor delay (present) , Dyslexia (present) , Asthma (present) , Otitis media with effusion (present) , Chronic constipation (present) , Thickened nuchal skin fold (present) … (more)
Motor delay (present) , Dyslexia (present) , Asthma (present) , Otitis media with effusion (present) , Chronic constipation (present) , Thickened nuchal skin fold (present) , Valvular pulmonary stenosis (present) , Hypotonia (present) , Muscle weakness (present) , Bilateral cryptorchidism (present) , Attention deficit hyperactivity disorder (present) (less)
Sex: male
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Pathogenic
(Aug 01, 2022)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246732.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
PTPN11: PP1:Strong, PS2, PM2, PP2, PP3, PS3:Supporting
Number of individuals with the variant: 6
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Pathogenic
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 1
Affected status: unknown
Allele origin:
maternal
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Institute of Immunology and Genetics Kaiserslautern
Accession: SCV005382197.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
ACMG Criteria: PP1, PP2, PP3, PM2, PS3, PS2, PM5; Variant found in a heterozygous state
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Pathogenic
(Jun 06, 2013)
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no assertion criteria provided
Method: literature only
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NOONAN SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034502.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 17, 2014 |
Comment on evidence:
In affected members of 3 families and in a sporadic case of Noonan syndrome (NS1; 163950), Tartaglia et al. (2001) found a 922A-G transition in … (more)
In affected members of 3 families and in a sporadic case of Noonan syndrome (NS1; 163950), Tartaglia et al. (2001) found a 922A-G transition in exon 8 of the PTPN11 gene, predicting an asn308-to-asp (N308D) amino acid change. This missense mutation affected the phosphotyrosine phosphatase (PTP) domain. In a comprehensive study of Tartaglia et al. (2002), about one-third of the patients who had mutations in the PTPN11 gene had this mutation, which was by far the most common. This was the mutation present in the large 3-generation family that was used originally to establish linkage to the locus on 12q. That codon 308 is a hotspot for Noonan syndrome was further indicated by the finding of an asn308-to-ser (176876.0004) missense mutation in 2 families (Tartaglia et al., 2002). In the cohort of Noonan syndrome patients studied by Tartaglia et al. (2002) noted that in their cohort, no patient carrying the N308D mutation was enrolled in special education. Kosaki et al. (2002) found this mutation in a Japanese patient. In 13 (23%) of 56 patients with Noonan syndrome, Jongmans et al. (2005) identified the N308D mutation, confirming the reputation of nucleotide 922 as a mutation hotspot. Among these 13 patients only 3 attended special school. Except for this suspected correlation with normal education, the phenotype observed in patients with the mutation at nucleotide 922 did not differ from the phenotype in patients with other mutations. Yoon et al. (2013) calculated that the de novo mutation frequency of the 922A-G (N308D) mutation exceeds the genome average A-G mutation frequency by more than 2,400-fold. Yoon et al. (2013) examined the spacial distribution of the mutation in testes of 15 unaffected men and found that the mutations were not uniformly distributed across each testis as would be the expected for a mutation hot spot but were highly clustered and showed an age-dependent germline mosaicism. Computational modeling that used different stem cell division schemes confirmed that the data were inconsistent with hypermutation, but consistent with germline selection: mutated spermatogonial stem cells gained an advantage that allowed them to increase in frequency. SHP-2, the protein encoded by PTPN11, interacts with the transcriptional activator STAT3 (102582). Given STAT3's function in mouse spermatogonial stem cells, Yoon et al. (2013) suggested that this interaction might explain the mutant's selective advantage by means of repression of stem cell differentiation signals. Repression of STAT3 activity by cyclin D1 (168461) might also play a role in providing a germline-selective advantage to spermatogonia for the recurrent mutations in the receptor tyrosine kinases that cause Apert syndrome (101200) and MEN2B (162300). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Rasopathy
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000196666.1
First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015 |
Comment:
Variant classified using ACMG guidelines
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Noonan syndrome 1
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001161845.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Observation 2:
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Noonan syndrome 1
Affected status: yes
Allele origin:
unknown
|
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV003840154.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Number of individuals with the variant: 1
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Likely pathogenic
(May 01, 2020)
|
no assertion criteria provided
Method: research
|
Thrombocytopenia
Abnormal bleeding
Affected status: yes
Allele origin:
germline
|
Birmingham Platelet Group; University of Birmingham
Accession: SCV001450861.1
First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020 |
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Pathogenic
(May 31, 2019)
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no assertion criteria provided
Method: research
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Noonan syndrome 1
Affected status: yes
Allele origin:
de novo
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Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
Accession: SCV001482406.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979484.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001980137.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036087.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(Oct 09, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004041681.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
|
|
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Molecular Genetics, Centre for Human Genetics
Accession: SCV004190082.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Number of individuals with the variant: 6
Secondary finding: no
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Pathogenic
(Apr 17, 2024)
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no assertion criteria provided
Method: clinical testing
|
PTPN11-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004784939.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The PTPN11 c.922A>G variant is predicted to result in the amino acid substitution p.Asn308Asp. This variant has been well documented to be causative for Noonan … (more)
The PTPN11 c.922A>G variant is predicted to result in the amino acid substitution p.Asn308Asp. This variant has been well documented to be causative for Noonan syndrome (see for example - Tartaglia et al. 2001. PubMed ID: 11704759). At PreventionGenetics, we identified this variant previously in several other patients with Noonan spectrum disorders. Functional studies demonstrate increased protein tyrosine phosphatase activity, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Fragale et al. 2004. PubMed ID: 14974085). Additionally, different amino acid substitutions affecting the same amino acid (p.Asn308Thr and p.Asn308Ser) have been reported in individuals with Noonan syndrome (Wilbe et al. 2017. PubMed ID: 28921562; Tartaglia et al. 2002. PubMed ID: 11992261). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13326/). This variant is interpreted as pathogenic. (less)
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not provided
(-)
|
no classification provided
Method: not provided
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Noonan syndrome 1
Affected status: not provided
Allele origin:
germline
|
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)
Accession: SCV000143819.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
|
|
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not provided
(-)
|
no classification provided
Method: literature only
|
Noonan syndrome 1
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000040937.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Comment:
Comment:
The PTPN11 p.Asn308Asp variant (rs28933386, ClinVar variant ID 13326) is frequently found in patients diagnosed with Noonan syndrome (Ezquita 2012, Jongmans 2005, Kosaki 2002, Papadopoulou 2012, Tafazoli 2018, Tartaglia 2001, Tartaglia 2002, Tartaglia 2006, Ueda 2017, van Nierop 2017, Zenker 2004), and co-segregates with affected individuals (Tartaglia 2002). The variant is located in the phospho-tyrosine phosphatase domain of PTPN11 (Qiu 2014, Tartaglia 2001), and additional missense variants at this residue have also been associated with Noonan syndrome (Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Asn308Asp protein indicates increased catalytic activity (Fragale 2004, Keilhack 2005, Qui 2014, Tartaglia 2006) due to stabilization of the active enzyme (Qiu 2014). This leads to over-activation of phospho-MEK and phospho-ERK signaling (Fragale 2004), consistent with the established disease mechanisms of Noonan syndrome. The p.Asn308Asp variant is therefore classified as pathogenic. References: Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 65(5):447-55. Fragale A et al. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat 2004 23(3):267-77. Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 19(8):870-4. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 280(35):30984-93. Kosaki K et al. PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab. 2002 87(8):3529-33. Papadopoulou A et al. Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. Eur J Pediatr. 2012 171(1):51-8. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 14:10. Tafazoli A et al. Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing. Adv Med Sci. 2018 Mar;63(1):87-93. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 29(4):465-8. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 70(6): 1555-1563. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 78(2): 279-290. Ueda K et al. Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. Am J Med Genet A. 2017 Sep;173(9):2346-2352. van Nierop JWI et al. Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11. Int J Pediatr Otorhinolaryngol. 2017 Jun;97:228-234. Zenker M et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004 144(3):368-74.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3.
Comment:
The c.922A>G;p.(Asn308Asp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13326; PMID: 11992261; 14974085; 15987685; 19509418; 20308328; 20979190; 11704759; 22465605) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:14974085, 15987685, 19509418, 20308328) - PS3. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 20979190; 11704759; 22465605) - PS2.The variant is present at low allele frequencies population databases (rs28933386– gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 11992261) - PP1_strong. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP1 strong, PP2 supporting, PP3 supporting
Comment:
The PTPN11 c.922A>G (p.Asn308Asp) variant has been reported to segregate with disease in many families with Noonan syndrome and related conditions (Tartaglia M et al). Experimental studies have shown that this missense change is located in the conserved protein-tyrosine phosphatase domain of the PTPN11 protein and results in higher levels of activity (Tartaglia M et al). This variant is reported with the allele frequency (0.0012%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar Pathogenic. The amino acid Asn at position 308 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asn308Asp in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Asn308Asp variant in PTPN11 is an established pathogenic variant for Noonan syndrome and has been reported in approximately 11-20% of individuals with Noonan syndrome across multiple studies (Tartaglia 2001 PMID: 11704759, Jongmans 2005 PMID: 15723289, Tartaglia 2006 PMID: 16358218, Jongmans 2011 PMID: 21407260, Ezquieta 2012 PMID: 22465605). In addition, de novo occurrences and germline mosaicism have been described (Tartaglia 2001 PMID: 11704759, Elalaoui 2010 PMID: 20979190, Ezquieta 2012 PMID: 22465605). This variant has been identified in 0.001% (3/251440) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreover, this variant has been classified as pathogenic on April 03, 2017 by the ClinGen-approved RASopathy expert panel (SCV000616374.3). In vitro functional studies provide some evidence that this variant impacts protein function (Fragale 2004 PMID: 14974085, Niihori 2005 PMID: 15834506). Additional variants involving this codon (p.Asn308Ser and p.Asn308Thr) have been identified in individuals with Noonan syndrome and are classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based on its frequency in affected individuals and de novo occurrences. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM5_Strong, PS3_Moderate.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene associated with Noonan syndrome are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the protein tyrosine phosphatase domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well established as a pathogenic variant for Noonan syndrome (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has been identified in >20 probands with Noonan syndrome and segregating with disease in at least 7 affected relatives (Tartaglia 2001 PMID:11704759, Tartaglia 2002 PMID:11992261, Brasil 2010 PMID:21340158, Jongmans 2011 PMID:21407260, Prada 2011 PMID:21567923, Ejarque 2015 PMID:25912702, van Trier 2016 PMID:27521173, van Nierop 2017 PMID:28483241). This variant is present in 3/246202 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28933386). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13326). Evolutionary conservation and computational predictive tools for this variant are unclear. However, functional studies have shown a deleterious effect of this variant on the protein (Fragale 2004 PMID:14974085, Oishi 2006 PMID:16399795, Qiu 2014 PMID:24628801). Of note, at least one other variant at this position (p.Asn308Ser) has been associated with disease at this position, supporting that this region is functionally significant. In summary, this variant is classified as pathogenic (high presence of affected probands, segregation studies, absence from controls, functional studies).
Comment:
Variant summary: PTPN11 c.922A>G (p.Asn308Asp) results in a conservative amino acid change located in the PTP type protein phosphatase of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251830 control chromosomes. c.922A>G has been reported in the literature in numerous individuals affected with Noonan Syndrome. These data indicate that the variant is very likely to be associated with disease. Residue 308 is located in the PTP domain and is reported as the most common residue affected in NS patients (N308D and N308S). Functional studies showed that this variant leads to a mild activation of the protein's catalytic activity (about 3-fold higher than WT; Keilhack_2005). 16 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
[ACMG/AMP/ClinGen RASopathy: PS2_VeryStrong, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2_VeryStrong], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].
Comment:
N308D is the most common variant causing Noonan syndrome (Tartaglia et al., 2002); Most individuals have mild or no cognitive impairment (Pierpont et al., 2009; Tartaglia et al., 2002); Published functional studies indicate altered local hydrogen bond network of the PTPN11 protein and increased basal phosphatase activity compared to wild-type protein (Qiu et al., 2014; Fragale et al., 2004); Classified as pathogenic by the ClinGen RASopathy Expert Panel (ClinVar SCV000616374.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 20308328, 16399795, 26607044, 21567923, 26377682, 27521173, 11704759, 20979190, 30294303, 28991257, 19352411, 21407260, 14974085, 15987685, 19509418, 25912702, 24628801, 11992261, 24803665, 26918529, 23726368, 24072241, 22822385, 19077116, 26785492, 21340158, 28135719, 28957739, 28650561, 28483241, 18253957, 29214238, 30355600, 26645620, 29848529, 30417923, 30050098, 29263817, 30287924, 29907801, 31219622, 31637070, 31560489, 32164556, 32054441, 32935436, 32150461, 32369273, 31216405, 32371413, 32581362, 31589614, 33300679, 33258288)
Comment:
PS3, PM1, PM5, PP2, PP3, PP4, PP5
Comment:
PS2, PS3, PS4, PP1, PP2, PP3, PM1, PM5
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013326). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 11704759,20979190,22465605) and co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID:11992261). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:14974085, 15987685, 19509418, 20308328). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.98). Different missense changes at the same codon (p.Asn308Ser, p.Asn308Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013327, VCV000040535). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has been identified in >20 probands with Noonan syndrome and segregating with disease in at least 7 affected relatives (Tartaglia 2001 PMID:11704759, Tartaglia 2002 PMID:11992261, Brasil 2010 PMID:21340158, Jongmans 2011 PMID:21407260, Prada 2011 PMID:21567923, Ejarque 2015 PMID:25912702, van Trier 2016 PMID:27521173, van Nierop 2017 PMID:28483241). This variant is present in 3/246202 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28933386). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13326). Evolutionary conservation and computational predictive tools for this variant are unclear. However, functional studies have shown a deleterious effect of this variant on the protein (Fragale 2004 PMID:14974085, Oishi 2006 PMID:16399795, Qiu 2014 PMID:24628801). Of note, at least one other variant at this position (p.Asn308Ser) has been associated with disease at this position, supporting that this region is functionally significant. In summary, this variant is classified as pathogenic (high presence of affected probands, segregation studies, absence from controls, functional studies).
Comment:
A Heterozygous Missense variant c.922A>G in Exon 8 of the PTPN11 gene that results in the amino acid substitution p.Asn308Asp was identified. The observed variant has a maximum allele frequency of 0.00001% in gnomAD exomes and novel in genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID:13326]. This variant has previously been reported for Noonan syndrome by Jeevana PA et al., 2020. For these reasons, this variant has been classified as Pathogenic.
Comment:
The PTPN11 c.922A>G (p.Asn308Asp) missense variant is one of the most common pathogenic variants associated with Noonan syndrome. In most cases, this variant occurs as the result of a de novo event, but also has been shown to segregate with disease in affected individuals within families (PMID: 11992261; 19352411; 20301303; 20979190; 22465605). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies demonstrate that this variant impacts protein function (PMID: 15987685; 19509418). This variant has been classified as pathogenic in ClinVar by several submitters, including the ClinGen RASopathy Expert Panel. This variant was identified in a de novo state. Based on the available evidence, the c.922A>G (p.Asn308Asp) variant is classified as pathogenic for Noonan syndrome.
Comment:
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 308 of the PTPN11 protein (p.Asn308Asp). This variant is present in population databases (rs28933386, gnomAD 0.004%). This missense change has been observed in individual(s) with Noonan syndrome and related conditions (PMID: 11704759, 16358218, 21340158, 21567923; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13326). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16358218, 19509418, 20308328). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.N308D pathogenic mutation (also known as c.922A>G), located in coding exon 8 of the PTPN11 gene, results from an A to G substitution at nucleotide position 922. The asparagine at codon 308 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was first reported in three families and one sporadic proband with Noonan syndrome; however, specific diagnostic criteria were not strictly defined in this study (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8). The Asn308 residue is located in the PTP (protein tyrosine phosphate) domain, and it has been described as a mutational hot spot, with p.N308D referred to as the most common Noonan syndrome mutation accounting for 25% of cases. In the same studies, functional in vitro analyses revealed that this alteration increases protein tyrosine phosphatase activity in the catalytic domain compared to wild type due to gain-of-function effects (Fragale A et al. Hum. Mutat., 2004 Mar;23:267-77; Qiu W et al. BMC Struct. Biol., 2014 Mar;14:10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The inherited heterozygous c.922A>G, p. (Asn308Asp) in PTPN11 is reported as one of the most common variants and accounts for 25% of Noonan syndrome cases. This c.922A>G variant has previously been identified in both de novo and inherited occurrences in individuals with Noonan syndrome [PMID:20979190, 22465605, 26645620, 32164556, 34411415, 35440950, 34194850] and found to be co-segregated with disease [PMID: 11992261]. The c.922A>G variant has been classified as Pathogenic for Noonan syndrome by ClinGen RASopathy Variant Curation Expert Panel [ClinVar ID: 13326] and observed in 5 allele (~0.0011% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.922A>G variant in PTPN11 is located in exon 8 of this 16-exon gene and predicted to replace an evolutionarily conserved asparagine amino acid with aspartic acid p. (Asn308Asp) in the protein tyrosine phosphatase (PTP) domain of the encoded protein and has been described as a mutational hot spot [PMID: 32164556,24628801]. In vitro functional studies demonstrated increased phosphatase activity indicating the gain-of-function effects in fibroblast cells carrying c.922A>G variant [PMID: 14974085, 15987685, 19509418, 20308328]. In silico predictions are in favor of damaging effect for p.(Asn308Asp) [(CADD v1.6 = 24.5, REVEL = 0.84)]. Other missense variants affecting the same p.(Asn308) residue have been reported in the literature (p.Asn308Ser) [PMID: 32164556] and ClinVar [ClinVar IDs: 13327] in individuals with Noonan syndrome. Based on available evidence this inherited heterozygous c.922A>G p.(Asn308Asp) in PTPN11 is classified as Pathogenic for Noonan syndrome 1.
Comment:
Criteria applied: PS2_VSTR,PS4,PS3_MOD,PP3
Comment:
PTPN11: PP1:Strong, PS2, PM2, PP2, PP3, PS3:Supporting
Comment:
ACMG Criteria: PP1, PP2, PP3, PM2, PS3, PS2, PM5; Variant found in a heterozygous state
Comment:
Variant classified using ACMG guidelines
Comment:
The PTPN11 c.922A>G variant is predicted to result in the amino acid substitution p.Asn308Asp. This variant has been well documented to be causative for Noonan syndrome (see for example - Tartaglia et al. 2001. PubMed ID: 11704759). At PreventionGenetics, we identified this variant previously in several other patients with Noonan spectrum disorders. Functional studies demonstrate increased protein tyrosine phosphatase activity, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Fragale et al. 2004. PubMed ID: 14974085). Additionally, different amino acid substitutions affecting the same amino acid (p.Asn308Thr and p.Asn308Ser) have been reported in individuals with Noonan syndrome (Wilbe et al. 2017. PubMed ID: 28921562; Tartaglia et al. 2002. PubMed ID: 11992261). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13326/). This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The c.922A>G (p.Asn308Asp) variant in PTPN11 has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 20979190, and 11704759, 22465605). The variant has co-segregated with disease in more than 7 family members (PP1_Strong; PMID: 11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn308Asp variant may impact the protein (PP3). Additionally, at least 2 functional studies have been concordant in showing that this variant may be deleterious to the protein (PS3; PMID 14974085, 15987685, 19509418, 20308328). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM2, PP1_Strong, PS2_VeryStrong, PS3.
Comment:
The PTPN11 p.Asn308Asp variant (rs28933386, ClinVar variant ID 13326) is frequently found in patients diagnosed with Noonan syndrome (Ezquita 2012, Jongmans 2005, Kosaki 2002, Papadopoulou 2012, Tafazoli 2018, Tartaglia 2001, Tartaglia 2002, Tartaglia 2006, Ueda 2017, van Nierop 2017, Zenker 2004), and co-segregates with affected individuals (Tartaglia 2002). The variant is located in the phospho-tyrosine phosphatase domain of PTPN11 (Qiu 2014, Tartaglia 2001), and additional missense variants at this residue have also been associated with Noonan syndrome (Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Asn308Asp protein indicates increased catalytic activity (Fragale 2004, Keilhack 2005, Qui 2014, Tartaglia 2006) due to stabilization of the active enzyme (Qiu 2014). This leads to over-activation of phospho-MEK and phospho-ERK signaling (Fragale 2004), consistent with the established disease mechanisms of Noonan syndrome. The p.Asn308Asp variant is therefore classified as pathogenic. References: Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 65(5):447-55. Fragale A et al. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat 2004 23(3):267-77. Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 19(8):870-4. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 280(35):30984-93. Kosaki K et al. PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab. 2002 87(8):3529-33. Papadopoulou A et al. Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. Eur J Pediatr. 2012 171(1):51-8. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 14:10. Tafazoli A et al. Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing. Adv Med Sci. 2018 Mar;63(1):87-93. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 29(4):465-8. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 70(6): 1555-1563. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 78(2): 279-290. Ueda K et al. Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. Am J Med Genet A. 2017 Sep;173(9):2346-2352. van Nierop JWI et al. Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11. Int J Pediatr Otorhinolaryngol. 2017 Jun;97:228-234. Zenker M et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004 144(3):368-74.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3.
Comment:
The c.922A>G;p.(Asn308Asp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13326; PMID: 11992261; 14974085; 15987685; 19509418; 20308328; 20979190; 11704759; 22465605) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:14974085, 15987685, 19509418, 20308328) - PS3. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 20979190; 11704759; 22465605) - PS2.The variant is present at low allele frequencies population databases (rs28933386– gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 11992261) - PP1_strong. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP1 strong, PP2 supporting, PP3 supporting
Comment:
The PTPN11 c.922A>G (p.Asn308Asp) variant has been reported to segregate with disease in many families with Noonan syndrome and related conditions (Tartaglia M et al). Experimental studies have shown that this missense change is located in the conserved protein-tyrosine phosphatase domain of the PTPN11 protein and results in higher levels of activity (Tartaglia M et al). This variant is reported with the allele frequency (0.0012%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar Pathogenic. The amino acid Asn at position 308 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asn308Asp in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Asn308Asp variant in PTPN11 is an established pathogenic variant for Noonan syndrome and has been reported in approximately 11-20% of individuals with Noonan syndrome across multiple studies (Tartaglia 2001 PMID: 11704759, Jongmans 2005 PMID: 15723289, Tartaglia 2006 PMID: 16358218, Jongmans 2011 PMID: 21407260, Ezquieta 2012 PMID: 22465605). In addition, de novo occurrences and germline mosaicism have been described (Tartaglia 2001 PMID: 11704759, Elalaoui 2010 PMID: 20979190, Ezquieta 2012 PMID: 22465605). This variant has been identified in 0.001% (3/251440) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreover, this variant has been classified as pathogenic on April 03, 2017 by the ClinGen-approved RASopathy expert panel (SCV000616374.3). In vitro functional studies provide some evidence that this variant impacts protein function (Fragale 2004 PMID: 14974085, Niihori 2005 PMID: 15834506). Additional variants involving this codon (p.Asn308Ser and p.Asn308Thr) have been identified in individuals with Noonan syndrome and are classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based on its frequency in affected individuals and de novo occurrences. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM5_Strong, PS3_Moderate.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene associated with Noonan syndrome are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the protein tyrosine phosphatase domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well established as a pathogenic variant for Noonan syndrome (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has been identified in >20 probands with Noonan syndrome and segregating with disease in at least 7 affected relatives (Tartaglia 2001 PMID:11704759, Tartaglia 2002 PMID:11992261, Brasil 2010 PMID:21340158, Jongmans 2011 PMID:21407260, Prada 2011 PMID:21567923, Ejarque 2015 PMID:25912702, van Trier 2016 PMID:27521173, van Nierop 2017 PMID:28483241). This variant is present in 3/246202 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28933386). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13326). Evolutionary conservation and computational predictive tools for this variant are unclear. However, functional studies have shown a deleterious effect of this variant on the protein (Fragale 2004 PMID:14974085, Oishi 2006 PMID:16399795, Qiu 2014 PMID:24628801). Of note, at least one other variant at this position (p.Asn308Ser) has been associated with disease at this position, supporting that this region is functionally significant. In summary, this variant is classified as pathogenic (high presence of affected probands, segregation studies, absence from controls, functional studies).
Comment:
Variant summary: PTPN11 c.922A>G (p.Asn308Asp) results in a conservative amino acid change located in the PTP type protein phosphatase of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251830 control chromosomes. c.922A>G has been reported in the literature in numerous individuals affected with Noonan Syndrome. These data indicate that the variant is very likely to be associated with disease. Residue 308 is located in the PTP domain and is reported as the most common residue affected in NS patients (N308D and N308S). Functional studies showed that this variant leads to a mild activation of the protein's catalytic activity (about 3-fold higher than WT; Keilhack_2005). 16 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
[ACMG/AMP/ClinGen RASopathy: PS2_VeryStrong, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2_VeryStrong], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].
Comment:
N308D is the most common variant causing Noonan syndrome (Tartaglia et al., 2002); Most individuals have mild or no cognitive impairment (Pierpont et al., 2009; Tartaglia et al., 2002); Published functional studies indicate altered local hydrogen bond network of the PTPN11 protein and increased basal phosphatase activity compared to wild-type protein (Qiu et al., 2014; Fragale et al., 2004); Classified as pathogenic by the ClinGen RASopathy Expert Panel (ClinVar SCV000616374.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 20308328, 16399795, 26607044, 21567923, 26377682, 27521173, 11704759, 20979190, 30294303, 28991257, 19352411, 21407260, 14974085, 15987685, 19509418, 25912702, 24628801, 11992261, 24803665, 26918529, 23726368, 24072241, 22822385, 19077116, 26785492, 21340158, 28135719, 28957739, 28650561, 28483241, 18253957, 29214238, 30355600, 26645620, 29848529, 30417923, 30050098, 29263817, 30287924, 29907801, 31219622, 31637070, 31560489, 32164556, 32054441, 32935436, 32150461, 32369273, 31216405, 32371413, 32581362, 31589614, 33300679, 33258288)
Comment:
PS3, PM1, PM5, PP2, PP3, PP4, PP5
Comment:
PS2, PS3, PS4, PP1, PP2, PP3, PM1, PM5
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013326). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 11704759,20979190,22465605) and co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID:11992261). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:14974085, 15987685, 19509418, 20308328). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.98). Different missense changes at the same codon (p.Asn308Ser, p.Asn308Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013327, VCV000040535). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has been identified in >20 probands with Noonan syndrome and segregating with disease in at least 7 affected relatives (Tartaglia 2001 PMID:11704759, Tartaglia 2002 PMID:11992261, Brasil 2010 PMID:21340158, Jongmans 2011 PMID:21407260, Prada 2011 PMID:21567923, Ejarque 2015 PMID:25912702, van Trier 2016 PMID:27521173, van Nierop 2017 PMID:28483241). This variant is present in 3/246202 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28933386). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13326). Evolutionary conservation and computational predictive tools for this variant are unclear. However, functional studies have shown a deleterious effect of this variant on the protein (Fragale 2004 PMID:14974085, Oishi 2006 PMID:16399795, Qiu 2014 PMID:24628801). Of note, at least one other variant at this position (p.Asn308Ser) has been associated with disease at this position, supporting that this region is functionally significant. In summary, this variant is classified as pathogenic (high presence of affected probands, segregation studies, absence from controls, functional studies).
Comment:
A Heterozygous Missense variant c.922A>G in Exon 8 of the PTPN11 gene that results in the amino acid substitution p.Asn308Asp was identified. The observed variant has a maximum allele frequency of 0.00001% in gnomAD exomes and novel in genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID:13326]. This variant has previously been reported for Noonan syndrome by Jeevana PA et al., 2020. For these reasons, this variant has been classified as Pathogenic.
Comment:
The PTPN11 c.922A>G (p.Asn308Asp) missense variant is one of the most common pathogenic variants associated with Noonan syndrome. In most cases, this variant occurs as the result of a de novo event, but also has been shown to segregate with disease in affected individuals within families (PMID: 11992261; 19352411; 20301303; 20979190; 22465605). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies demonstrate that this variant impacts protein function (PMID: 15987685; 19509418). This variant has been classified as pathogenic in ClinVar by several submitters, including the ClinGen RASopathy Expert Panel. This variant was identified in a de novo state. Based on the available evidence, the c.922A>G (p.Asn308Asp) variant is classified as pathogenic for Noonan syndrome.
Comment:
This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 308 of the PTPN11 protein (p.Asn308Asp). This variant is present in population databases (rs28933386, gnomAD 0.004%). This missense change has been observed in individual(s) with Noonan syndrome and related conditions (PMID: 11704759, 16358218, 21340158, 21567923; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13326). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16358218, 19509418, 20308328). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.N308D pathogenic mutation (also known as c.922A>G), located in coding exon 8 of the PTPN11 gene, results from an A to G substitution at nucleotide position 922. The asparagine at codon 308 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was first reported in three families and one sporadic proband with Noonan syndrome; however, specific diagnostic criteria were not strictly defined in this study (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8). The Asn308 residue is located in the PTP (protein tyrosine phosphate) domain, and it has been described as a mutational hot spot, with p.N308D referred to as the most common Noonan syndrome mutation accounting for 25% of cases. In the same studies, functional in vitro analyses revealed that this alteration increases protein tyrosine phosphatase activity in the catalytic domain compared to wild type due to gain-of-function effects (Fragale A et al. Hum. Mutat., 2004 Mar;23:267-77; Qiu W et al. BMC Struct. Biol., 2014 Mar;14:10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The inherited heterozygous c.922A>G, p. (Asn308Asp) in PTPN11 is reported as one of the most common variants and accounts for 25% of Noonan syndrome cases. This c.922A>G variant has previously been identified in both de novo and inherited occurrences in individuals with Noonan syndrome [PMID:20979190, 22465605, 26645620, 32164556, 34411415, 35440950, 34194850] and found to be co-segregated with disease [PMID: 11992261]. The c.922A>G variant has been classified as Pathogenic for Noonan syndrome by ClinGen RASopathy Variant Curation Expert Panel [ClinVar ID: 13326] and observed in 5 allele (~0.0011% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.922A>G variant in PTPN11 is located in exon 8 of this 16-exon gene and predicted to replace an evolutionarily conserved asparagine amino acid with aspartic acid p. (Asn308Asp) in the protein tyrosine phosphatase (PTP) domain of the encoded protein and has been described as a mutational hot spot [PMID: 32164556,24628801]. In vitro functional studies demonstrated increased phosphatase activity indicating the gain-of-function effects in fibroblast cells carrying c.922A>G variant [PMID: 14974085, 15987685, 19509418, 20308328]. In silico predictions are in favor of damaging effect for p.(Asn308Asp) [(CADD v1.6 = 24.5, REVEL = 0.84)]. Other missense variants affecting the same p.(Asn308) residue have been reported in the literature (p.Asn308Ser) [PMID: 32164556] and ClinVar [ClinVar IDs: 13327] in individuals with Noonan syndrome. Based on available evidence this inherited heterozygous c.922A>G p.(Asn308Asp) in PTPN11 is classified as Pathogenic for Noonan syndrome 1.
Comment:
Criteria applied: PS2_VSTR,PS4,PS3_MOD,PP3
Comment:
PTPN11: PP1:Strong, PS2, PM2, PP2, PP3, PS3:Supporting
Comment:
ACMG Criteria: PP1, PP2, PP3, PM2, PS3, PS2, PM5; Variant found in a heterozygous state
Comment:
Variant classified using ACMG guidelines
Comment:
The PTPN11 c.922A>G variant is predicted to result in the amino acid substitution p.Asn308Asp. This variant has been well documented to be causative for Noonan syndrome (see for example - Tartaglia et al. 2001. PubMed ID: 11704759). At PreventionGenetics, we identified this variant previously in several other patients with Noonan spectrum disorders. Functional studies demonstrate increased protein tyrosine phosphatase activity, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Fragale et al. 2004. PubMed ID: 14974085). Additionally, different amino acid substitutions affecting the same amino acid (p.Asn308Thr and p.Asn308Ser) have been reported in individuals with Noonan syndrome (Wilbe et al. 2017. PubMed ID: 28921562; Tartaglia et al. 2002. PubMed ID: 11992261). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13326/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Undiagnosed RASopathies in infertile men. | Juchnewitsch AG | Frontiers in endocrinology | 2024 | DOI: 10.3389/fendo.2024.1312357 |
| High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations. | Belanger Deloge R | European journal of human genetics : EJHG | 2023 | PMID: 36474027 |
| Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus. | Sy MR | American journal of medical genetics. Part A | 2022 | PMID: 36135330 |
| Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it? | Mellis R | BJOG : an international journal of obstetrics and gynaecology | 2022 | PMID: 34411415 |
| Noonan Syndrome. | Adam MP | - | 2022 | PMID: 20301303 |
| Lack of Catch-Up Growth with Growth Hormone Treatment in a Child Born Small for Gestational Age Leading to a Diagnosis of Noonan Syndrome with a Pathogenic PTPN11 Variant. | Olivieri DJ | Case reports in endocrinology | 2021 | PMID: 34194850 |
| Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| Comprehensive analysis of mitochondrial and nuclear DNA variations in patients affected by hemoglobinopathies: A pilot study. | Barbanera Y | PloS one | 2020 | PMID: 33091040 |
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. | Athota JP | BMC medical genetics | 2020 | DOI: 10.1186/s12881-020-0986-5 |
| Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. | Athota JP | BMC medical genetics | 2020 | PMID: 32164556 |
| A First Case Report of Subependymoma in PTPN11 Mutation-Associated Noonan Syndrome. | Boonyawat B | Case reports in neurological medicine | 2019 | PMID: 31637070 |
| Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina. | Chinton J | Archivos argentinos de pediatria | 2019 | PMID: 31560489 |
| Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. | Li X | Clinical genetics | 2019 | PMID: 31219622 |
| Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. | Bessis D | The British journal of dermatology | 2019 | PMID: 30417923 |
| Putting genome-wide sequencing in neonates into perspective. | van der Sluijs PJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30287924 |
| Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. | Leach NT | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29907801 |
| Compound Heterozygosity for Hb D-Ibadan (HBB: c.263C>A) and Hb C (HBB: c.19G>A). | Kundrapu S | Hemoglobin | 2018 | PMID: 30604644 |
| Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes. | Maher GJ | Genome research | 2018 | PMID: 30355600 |
| An Association of PTPN11 and SHOX Mutations in a Male Presenting With Syndromic Growth Failure. | Savarese E | Frontiers in endocrinology | 2018 | PMID: 30294303 |
| Giant cell lesion of the jaw as a presenting feature of Noonan syndrome. | Sinnott BP | BMJ case reports | 2018 | PMID: 29848529 |
| Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing. | Tafazoli A | Advances in medical sciences | 2018 | PMID: 28957739 |
| Redox Regulation of a Gain-of-Function Mutation (N308D) in SHP2 Noonan Syndrome. | Machado LESF | ACS omega | 2017 | PMID: 29214238 |
| Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. | Jin SC | Nature genetics | 2017 | PMID: 28991257 |
| Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. | Ueda K | American journal of medical genetics. Part A | 2017 | PMID: 28650561 |
| Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11. | van Nierop JWI | International journal of pediatric otorhinolaryngology | 2017 | PMID: 28483241 |
| Prevalence and architecture of de novo mutations in developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2017 | PMID: 28135719 |
| Clinical detection of deletion structural variants in whole-genome sequences. | Noll AC | NPJ genomic medicine | 2016 | PMID: 29263817 |
| Ocular Manifestations of Noonan Syndrome: A Prospective Clinical and Genetic Study of 25 Patients. | van Trier DC | Ophthalmology | 2016 | PMID: 27521173 |
| Mild Microcytic Anemia in an Infant with a Compound Heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A). | Boucher MO | Hemoglobin | 2016 | PMID: 27117572 |
| Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder. | Hakami F | Prenatal diagnosis | 2016 | PMID: 26918529 |
| Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations. | Atik T | Indian journal of pediatrics | 2016 | PMID: 26817465 |
| Hereditary Persistence of Fetal Hemoglobin Caused by Single Nucleotide Promoter Mutations in Sickle Cell Trait and Hb SC Disease. | Akinbami AO | Hemoglobin | 2016 | PMID: 26372199 |
| De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. | Homsy J | Science (New York, N.Y.) | 2015 | PMID: 26785492 |
| Cryptic 13q34 and 4q35.2 Deletions in an Italian Family. | Riccardi F | Cytogenetic and genome research | 2015 | PMID: 26645620 |
| [Arnold-Chiari malformation in Noonan syndrome and other syndromes of the RAS/MAPK pathway]. | Ejarque I | Revista de neurologia | 2015 | PMID: 25912702 |
| Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. | Yu ZH | Biochemistry | 2014 | PMID: 24935154 |
| Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. | Kiel C | Molecular systems biology | 2014 | PMID: 24803665 |
| Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). | Qiu W | BMC structural biology | 2014 | PMID: 24628801 |
| Acute lymphoblastic leukemia developing in a patient with Noonan syndrome harboring a PTPN11 germline mutation. | Sakamoto K | Journal of pediatric hematology/oncology | 2014 | PMID: 24072241 |
| Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection. | Yoon SR | American journal of human genetics | 2013 | PMID: 23726368 |
| The clinical and laboratory spectrum of Hb C [β6(A3)Glu→Lys, GAG>AAG] disease. | Cook CM | Hemoglobin | 2013 | PMID: 23297836 |
| Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. | Ezquieta B | Revista espanola de cardiologia (English ed.) | 2012 | PMID: 22465605 |
| Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. | Papadopoulou A | European journal of pediatrics | 2012 | PMID: 21590266 |
| RASopathies: Clinical Diagnosis in the First Year of Life. | Digilio MC | Molecular syndromology | 2011 | PMID: 22190897 |
| Lethal presentation of neurofibromatosis and Noonan syndrome. | Prada CE | American journal of medical genetics. Part A | 2011 | PMID: 21567923 |
| Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. | Bowen ME | PLoS genetics | 2011 | PMID: 21533187 |
| Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. | Jongmans MC | European journal of human genetics : EJHG | 2011 | PMID: 21407260 |
| Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype? | Brasil AS | Arquivos brasileiros de endocrinologia e metabologia | 2010 | PMID: 21340158 |
| Germinal mosaicism in Noonan syndrome: A family with two affected siblings of normal parents. | Elalaoui SC | American journal of medical genetics. Part A | 2010 | PMID: 20979190 |
| Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling. | Edouard T | Molecular and cellular biology | 2010 | PMID: 20308328 |
| Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. | Zhang W | The Journal of biological chemistry | 2009 | PMID: 19509418 |
| SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions. | Beneteau C | European journal of human genetics : EJHG | 2009 | PMID: 19352411 |
| Cognitive profile of disorders associated with dysregulation of the RAS/MAPK signaling cascade. | Cesarini L | American journal of medical genetics. Part A | 2009 | PMID: 19133693 |
| Genotype differences in cognitive functioning in Noonan syndrome. | Pierpont EI | Genes, brain, and behavior | 2009 | PMID: 19077116 |
| Newborn screening for hemoglobinopathies in California. | Michlitsch J | Pediatric blood & cancer | 2009 | PMID: 19061217 |
| Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients. | Ferreira LV | Clinical endocrinology | 2008 | PMID: 18331608 |
| Hepatoblastoma in a Noonan syndrome patient with a PTPN11 mutation. | Yoshida R | Pediatric blood & cancer | 2008 | PMID: 18253957 |
| Mutation analysis of the genes involved in the Ras-mitogen-activated protein kinase (MAPK) pathway in Korean patients with Noonan syndrome. | Lee ST | Clinical genetics | 2007 | PMID: 17661820 |
| [Phenotype variability in Noonan syndrome patients with and without PTPN11 mutation]. | Ferreira LV | Arquivos brasileiros de endocrinologia e metabologia | 2007 | PMID: 17546245 |
| The spectrum of cardiac anomalies in Noonan syndrome as a result of mutations in the PTPN11 gene. | Sznajer Y | Pediatrics | 2007 | PMID: 17515436 |
| Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. | Hung CS | Journal of the Formosan Medical Association = Taiwan yi zhi | 2007 | PMID: 17339163 |
| Germline gain-of-function mutations in SOS1 cause Noonan syndrome. | Roberts AE | Nature genetics | 2007 | PMID: 17143285 |
| PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype. | Bertola DR | Genetic testing | 2006 | PMID: 17020470 |
| A PTPN11 gene mutation (Y63C) causing Noonan syndrome is not associated with short stature in general population. | Takahashi I | The Tohoku journal of experimental medicine | 2006 | PMID: 16498234 |
| Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations. | Oishi K | Human molecular genetics | 2006 | PMID: 16399795 |
| PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. | Kontaridis MI | The Journal of biological chemistry | 2006 | PMID: 16377799 |
| Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. | Tartaglia M | American journal of human genetics | 2006 | PMID: 16358218 |
| Noonan syndrome: relationships between genotype, growth, and growth factors. | Limal JM | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16263833 |
| Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. | Keilhack H | The Journal of biological chemistry | 2005 | PMID: 15987685 |
| PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome. | Ferreira LV | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 15956085 |
| Acute myeloid leukemia in an adult Noonan syndrome patient with PTPN11 mutation. | Matsubara K | American journal of hematology | 2005 | PMID: 15929108 |
| Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. | Niihori T | Journal of human genetics | 2005 | PMID: 15834506 |
| Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature. | Jongmans M | American journal of medical genetics. Part A | 2005 | PMID: 15723289 |
| Genetics and variation in phenotype in Noonan syndrome. | Jongmans M | Hormone research | 2004 | PMID: 15539800 |
| Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. | Tartaglia M | American journal of human genetics | 2004 | PMID: 15248152 |
| Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome. | Yoshida R | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15240615 |
| Genotype-phenotype correlations in Noonan syndrome. | Zenker M | The Journal of pediatrics | 2004 | PMID: 15001945 |
| Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. | Fragale A | Human mutation | 2004 | PMID: 14974085 |
| Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. | Sarkozy A | Journal of medical genetics | 2003 | PMID: 12960218 |
| Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. | Tartaglia M | Nature genetics | 2003 | PMID: 12717436 |
| Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. | Musante L | European journal of human genetics : EJHG | 2003 | PMID: 12634870 |
| PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. | Kosaki K | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12161469 |
| PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. | Tartaglia M | American journal of human genetics | 2002 | PMID: 11992261 |
| Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. | Tartaglia M | Nature genetics | 2001 | PMID: 11704759 |
| Genetic implications of the interaction of two types of beta-thalassemia genes in a patient with thalassemia major. | Russo G | Blood | 1973 | PMID: 4746100 |
| A family with S and C hemoglobins and the hereditary persistence of F hemoglobin. A comparison of C thalassemia disease with the CF syndrome. | SCHNEIDER RG | The New England journal of medicine | 1961 | PMID: 13908956 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6525f07c-2ebf-4229-9447-62d126ad46cd | - | - | - | - |
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Text-mined citations for rs28933386 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.