The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID: 25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 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). 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): PS2_VeryStrong, PS3, PS4, PM2, PP2.
ClinVar Genomic variation as it relates to human health
NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly)
Variation ID: 6821 Accession: VCV000006821.93
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q25.2 10: 110964362 (GRCh38) [ NCBI UCSC ] 10: 112724120 (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 Apr 1, 2014 Nov 3, 2024 Apr 3, 2017 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007373.4:c.4A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_031399.2:p.Ser2Gly missense NM_001269039.2:c.4A>G NM_001269039.3:c.4A>G NP_001255968.1:p.Ser2Gly missense NM_001324336.2:c.4A>G NP_001311265.1:p.Ser2Gly missense NM_001324337.2:c.4A>G NP_001311266.1:p.Ser2Gly missense NC_000010.11:g.110964362A>G NC_000010.10:g.112724120A>G NG_028922.1:g.49820A>G LRG_753:g.49820A>G LRG_753t1:c.4A>G LRG_753p1:p.Ser2Gly Q9UQ13:p.Ser2Gly - Protein change
- S2G
- Other names
-
p.S2G:AGT>GGT
NM_007373.3(SHOC2):c.4A>G
- Canonical SPDI
- NC_000010.11:110964361: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.
-
The Genome Aggregation Database (gnomAD) 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. |
|||
| SHOC2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
517 | 555 | |
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 (23) |
reviewed by expert panel
|
Apr 3, 2017 | RCV000007223.49 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2024 | RCV000149834.23 | |
| Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
May 27, 2022 | RCV000213000.52 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 26, 2015 | RCV000208379.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 23, 2017 | RCV000624656.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 22, 2018 | RCV000853278.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 30, 2022 | RCV002221469.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 8, 2021 | RCV001813181.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV003330311.3 | |
|
SHOC2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 25, 2024 | RCV004752691.1 |
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-like disorder with loose anagen hair 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000616382.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; … (more)
The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID: 25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 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). 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): PS2_VeryStrong, PS3, PS4, PM2, PP2. (less)
|
|
|
Pathogenic
(Mar 13, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan-like syndrome with loose anagen hair
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000248876.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
|
|
Pathogenic
(Jan 26, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000264222.2
First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Sep 11, 2014)
|
criteria provided, single submitter
Method: research
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
de novo
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000265524.2 First in ClinVar: Mar 11, 2016 Last updated: May 29, 2016 |
Clinical Features:
Failure to thrive (present) , Facial dysmorphism (present) , Intellectual disability, moderate (present)
|
|
|
Pathogenic
(May 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611318.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Pathogenic
(Jun 15, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000332269.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(Jul 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000920499.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
|
|
|
Pathogenic
(Jan 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
de novo
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965711.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
|
|
|
Pathogenic
(Dec 03, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062456.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The p.Ser2Gly variant in SHOC2 is an established pathogenic variant for Noonan s yndrome with loose anagen hair. The variant was identified in >40 affected … (more)
The p.Ser2Gly variant in SHOC2 is an established pathogenic variant for Noonan s yndrome with loose anagen hair. The variant was identified in >40 affected indiv iduals across multiple studies and in multiple cases was shown to be de novo (Co rdeddu 2009, Komatsuzaki 2010, Gripp 2013, LMM data). It has not been identified large population studies. In vitro functional studies provide some evidence tha t the p.Ser2Gly variant impacts protein function (Cordeddu 2009). In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. (less)
Number of individuals with the variant: 30
|
|
|
Pathogenic
(Feb 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996110.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This variant has been previously reported as a de novo change in multiple unrelated patients with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 25331583). … (more)
This variant has been previously reported as a de novo change in multiple unrelated patients with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 25331583). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). It is present in one heterozygote in the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, this variant is classified as pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 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: SCV000699328.2
First in ClinVar: Mar 17, 2018 Last updated: Jun 22, 2020 |
Comment:
Variant summary: SHOC2 c.4A>G (p.Ser2Gly) results in a non-conservative amino acid change in the encoded protein sequence, located in the N-terminal region. Four of five … (more)
Variant summary: SHOC2 c.4A>G (p.Ser2Gly) results in a non-conservative amino acid change in the encoded protein sequence, located in the N-terminal region. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248040 control chromosomes. The variant has been reported in literature as one of the most recurrent mutations found in patients with NS or NS-related disorders. It is predominantly found in patients with Noonan-like syndrome with loose anagen hair. The variant was proven to be de novo in multiple patients strongly supporting its pathogenicity. From functional studies this variant was found to introduce an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2-S2G in vitro enhanced MAPK activation in a cell type specific fashion. Induction of SHOC2-S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype associated with aberrant signaling (Cordeddu_2009). In other functional study, the SHOC2-S2G mutant did not rescue ERK1/2 activation in Shoc2-depleted cells and the mutant was not located in late endosomes, however it was present on the plasma membrane and early endosomes (Galperin_2012). 13 clinical diagnostic laboratories (including one expert panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
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: SCV001447732.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Large fontanelles (present) , Hypotonia (present) , Failure to thrive (present) , Low posterior hairline (present) , Curly eyelashes (present)
Sex: male
|
|
|
Pathogenic
(Nov 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367708.2
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: PS3,PM2,PP2,PP3,PP4,PP5.
|
|
|
Pathogenic
(Feb 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984384.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
Comment:
The p.Ser2Gly missense variant in SHOC2 has been previously reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy … (more)
The p.Ser2Gly missense variant in SHOC2 has been previously reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PMIDs: 19684605 21548061 23918763 22528146). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PMID:19684605). This variant was identified in 1/31384 individuals in the Genome Aggregation Database (gnomAD). The variant is located in the SHOC2 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 (PMID: 29493581). Finally this variant has been classified as pathogenic by several clinical laboratories and by the FDA recognized ClinGen RASopathy Expert Panel (ClinVar ID: 6821). In summary this variant meets our criteria to be classified as pathogenic. (less)
|
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002012001.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 22528146, 21548061, … (more)
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 22528146, 21548061, 23918763, 19684605, 25563136, 24458587, PS2, PS4). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19684605, PS3). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000319, PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Brittle hair (present) , Thick eyebrow (present) , Relative macrocephaly (present) , Webbed neck (present) , Low-set ears (present) , Pulmonic stenosis (present) , Grade … (more)
Brittle hair (present) , Thick eyebrow (present) , Relative macrocephaly (present) , Webbed neck (present) , Low-set ears (present) , Pulmonic stenosis (present) , Grade I preterm intraventricular hemorrhage (present) (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Noonan syndrome-like disorder with loose anagen hair 1
Pectus excavatum
Explanation for multiple conditions: Co-occurring.
The variant causes a combination of distinct diseases; this scenario is expected to be rare. (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Accession: SCV004037443.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Clinical Features:
Hypertelorism (present) , Downslanted palpebral fissures (present) , Ptosis (present) , Long eyelashes (present) , Optic nerve hypoplasia (present) , Global developmental delay (present) , … (more)
Hypertelorism (present) , Downslanted palpebral fissures (present) , Ptosis (present) , Long eyelashes (present) , Optic nerve hypoplasia (present) , Global developmental delay (present) , Failure to thrive (present) , Ventricular septal defect (present) , Pulmonic stenosis (present) , Fine hair (present) , Decreased circulating antibody concentration (present) , Abnormality of the palmar creases (present) , Abnormal thalamus morphology (present) , Feeding difficulties (present) , Persistent fever (present) , Autosomal dominant inheritance (present) (less)
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253914.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2 of the SHOC2 protein (p.Ser2Gly). … (more)
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2 of the SHOC2 protein (p.Ser2Gly). This variant is present in population databases (rs267607048, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 20882035, 22995099, 23918763, 25123707, 25331583). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6821). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SHOC2 function (PMID: 19684605, 22606262). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805081.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198234.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Likely pathogenic
(Jul 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
unknown
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000263045.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 1
Clinical Features:
Short stature (present) , Sparse anagen hair (present) , Skin exzema (present) , Facial dysmorphism (present) , Mental retardation (present) , Developmental delay (present) , … (more)
Short stature (present) , Sparse anagen hair (present) , Skin exzema (present) , Facial dysmorphism (present) , Mental retardation (present) , Developmental delay (present) , Dark skin color (present) (less)
Age: 0-9 years
Sex: male
|
|
|
Likely pathogenic
(Nov 26, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan-like syndrome with loose anagen hair
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255466.2 First in ClinVar: Oct 11, 2015 Last updated: Mar 11, 2016 |
Age: 0-9 years
Sex: male
Ethnicity/Population group: Hawaiian
Testing laboratory: UCLA Clinical Genomics Center
|
|
|
Pathogenic
(Sep 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714366.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS2, PS3, PS4, PM6_Strong, PM1, PP2
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
de novo
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976983.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PS2, PM2, PP3, PP5
|
|
|
Pathogenic
(Jan 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
de novo
|
Centogene AG - the Rare Disease Company
Accession: SCV002059626.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
|
|
|
Pathogenic
(Jan 08, 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: SCV002060971.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
|
Pathogenic
(Mar 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 4
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002499159.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
PS2, PS4, PM2
|
|
|
Pathogenic
(Aug 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512520.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS2 very strong, PS3 moderate, PS4 moderate, PM2 moderate, PP2 supporting
Geographic origin: Brazil
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: unknown
Allele origin:
de novo
|
Genomic Medicine Lab, University of California San Francisco
Study: CSER
Accession: SCV002576361.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
|
|
|
Pathogenic
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 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: SCV002767174.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome-like with loose anagen hair (MIM#607721). Missense variants in this gene result in enhanced MAPK activation (OMIM, PMID: 19684605). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and is observed in de novo patients with RASopathy (ClinVar, PMID: 25331583). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have demonstrated this variant causes impaired nuclear translocation and MAPK activation (PMID: 19684605). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(May 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002817221.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 19684605, 25846317, 25331583, 25123707). The … (more)
This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 19684605, 25846317, 25331583, 25123707). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 19684605, 22606262).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
|
|
|
Pathogenic
(Feb 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741813.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Delayed speech and language development (present) , Muscular hypotonia (present) , Pulmonic stenosis (disease) (present) , Patent ductus arteriosus (present) … (more)
Global developmental delay (present) , Delayed speech and language development (present) , Muscular hypotonia (present) , Pulmonic stenosis (disease) (present) , Patent ductus arteriosus (present) , Secundum atrial septal defect (present) , Postnatal growth retardation (present) , Oral-pharyngeal dysphagia (present) , Relative macrocephaly (present) , Ptosis (present) , Amblyopia (present) , Esotropia (present) , Nephrolithiasis (present) , Hydronephrosis (present) , Bilateral conductive hearing impairment (present) , Reduced subcutaneous adipose tissue (present) , Sparse scalp hair (present) , Low-set ears (present) , Crumpled ear (present) (less)
Sex: female
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Intellectual disability, moderate (present) , Muscular hypotonia (present) , Failure to thrive (present) , Relative macrocephaly (present) , Tachypnea (present) … (more)
Global developmental delay (present) , Intellectual disability, moderate (present) , Muscular hypotonia (present) , Failure to thrive (present) , Relative macrocephaly (present) , Tachypnea (present) , Obstructive sleep apnea syndrome (present) , Hearing impairment (present) , Hypertelorism (present) , Long palpebral fissure (present) , Cutis laxa (present) , Sparse hair (present) , Ureteropelvic junction obstruction (present) , Abnormality of the sternum (present) , Poor appetite (present) (less)
Sex: male
Ethnicity/Population group: Hispanic
Observation 3:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Hispanic/Polish
|
|
|
Pathogenic
(May 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209051.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Located in the critical functional domain S2 and inhibits SHOC2 function by impairing proper cellular localization of the protein (Galperin et al., 2012); In silico … (more)
Located in the critical functional domain S2 and inhibits SHOC2 function by impairing proper cellular localization of the protein (Galperin et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25858597, 22419608, 26350204, 24803665, 31501239, 19684605, 22606262, 25846317, 25563136, 21548061, 24033266, 25326637, 24458596, 24458587, 25331583, 23918763, 25123707, 26096762, 22528146, 26607044, 26519477, 20882035, 22995099, 28680615, 28554332, 24124081, 29737035, 29948256, 30732632, 30240112, 30417923, 30050098, 29907801, 31219622, 30962759, 31584751, 31628766, 31019026, 32005694, 33318624, 34008892, 33300679, 33502061, 32978145, 33240318, 32870709, 34006472, 31785789) (less)
|
|
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Pathogenic
(Feb 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000807267.3
First in ClinVar: Dec 19, 2017 Last updated: Mar 11, 2023 |
|
|
|
Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: research
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: yes
Allele origin:
germline
|
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV004024492.2
First in ClinVar: Aug 19, 2023 Last updated: Nov 11, 2023 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171888.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
Comment:
The missense c.4A>G(p.Ser2Gly) variant in SHOC2 gene has been reported previously in individual(s) affected with Noonan syndrome with loose anagen hair (Gripp KW, et. al., … (more)
The missense c.4A>G(p.Ser2Gly) variant in SHOC2 gene has been reported previously in individual(s) affected with Noonan syndrome with loose anagen hair (Gripp KW, et. al., 2013; Choi JH, et. al., 2015). Functional studies indicate that this variant has a damaging effect on the gene or the gene product (Cordeddu V, et. al., 2009). The p.Ser2Gly variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been submitted to ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Ser2Gly in SHOC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 2 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605107.3
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The SHOC2 c.4A>G; p.Ser2Gly variant (rs267607048) has been reported in multiple individuals diagnosed with Noonan-like syndrome with loose anagen hair, and often identified as a … (more)
The SHOC2 c.4A>G; p.Ser2Gly variant (rs267607048) has been reported in multiple individuals diagnosed with Noonan-like syndrome with loose anagen hair, and often identified as a de novo alteration (Cordeddu 2009, Komatsuzaki 2010, Ekvall 2011, Gripp 2013, Baldassare 2014). Functional characterization of the p.Ser2Gly protein indicates enhanced myristoylation, and aberrant targeting of the SHOC2 to the cell membrane in the absence of growth factor signaling (Cordeddu 2009). This results in an increase in basal and growth-factor stimulated ERK phosphorylation (Cordeddu 2009), consistent with the established disease mechanisms. The variant is classified as pathogenic by many sources in the ClinVar database (Variation ID: 6821) is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is classified as pathogenic. References: Baldassarre G et al. Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation. Am J Med Genet A. 2014 Dec;164A(12):3120-5. PMID: 25331583. Cordeddu V et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009 Sep;41(9):1022-6. PMID: 19684605. Ekvall S et al. Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. Am J Med Genet A. 2011 Jun;155A(6):1217-24. PMID: 21548061. Gripp KW et al. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. Am J Med Genet A. 2013 Oct;161A(10):2420-30. PMID: 23918763. Komatsuzaki S et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 2010 Dec;55(12):801-9. PMID: 20882035. (less)
|
|
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Pathogenic
(Jan 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246712.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 7
|
|
|
Pathogenic
(Sep 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome-like disorder with loose anagen hair 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Palindrome, Gene Kavoshgaran Aria
Accession: SCV005382615.1
First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024 |
Clinical Features:
Global developmental delay (present) , Intellectual disability (present) , Poor speech (present) , Strabismus (present)
Secondary finding: no
|
|
|
Pathogenic
(Oct 01, 2013)
|
no assertion criteria provided
Method: literature only
|
NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027419.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 03, 2020 |
Comment on evidence:
In 25 patients with a Noonan syndrome-like disorder with loose anagen hair (NSLH1; 607721), Cordeddu et al. (2009) identified heterozygosity for a 4A-G transition in … (more)
In 25 patients with a Noonan syndrome-like disorder with loose anagen hair (NSLH1; 607721), Cordeddu et al. (2009) identified heterozygosity for a 4A-G transition in exon 2 of the SHOC2 gene, resulting in a ser2-to-gly (S2G) substitution. The mutation was shown to be de novo in the 15 patients for whom parental DNA was available. Functional studies demonstrated that the S2G mutation introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. In vitro expression of mutant SHOC2 enhanced MAPK (see 176948) activation in a cell type-specific fashion. Induction of mutant SHOC2 in C. elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. In a male infant with typical dysmorphic facial features and other signs of Noonan syndrome, who died of congestive heart failure at 4 months of age, Hoban et al. (2012) identified heterozygosity for a de novo S2G mutation in SHOC2. The authors noted that the 'loose anagen hair' phenotype and skin features previously reported in patients with the S2G mutation were not present in this young infant, and stated that the cardiac anomaly expanded the clinical phenotype associated with the SHOC2 mutation. In 5 unrelated children with Noonan syndrome-like disorder and loose anagen hair, Gripp et al. (2013) identified heterozygosity for the S2G mutation in the SHOC2 gene. The mutation was shown to have occurred de novo in 2 of the patients. In 8 unrelated patients with Noonan syndrome-like disorder and loose anagen hair, Komatsuzaki et al. (2010) identified heterozygosity for the S2G mutation, which was shown to have arisen de novo in the 3 patients for whom parental DNA was available. The authors noted that short stature, relative macrocephaly, hypertelorism, low-set ears, sparse/easily pluckable hair, and a variety of skin abnormalities, including dark skin and atopic dermatitis, were commonly seen in patients positive for the S2G mutation. Young et al. (2018) studied the SHOC2 S2G mutation in HEK293T cells and observed increased ability of the mutant protein to interact with MRAS (608435) and PP1 (601790) compared to wildtype SHOC2. In cotransfection assays, the S2G mutant also efficiently dephosphorylated positions S365 in BRAF (164757) and S259 in CRAF (164760). In addition, when reexpressed in SHOC2-knockout DLD1 cells, the S2G mutant decreased the higher basal levels of S365-BRAF and S259-CRAF phosphorylation as well as the impaired epidermal growth factor (EGF; 131530)-induced ERK (see 601795) pathway activation caused by SHOC2 ablation. Serum-starved DLD1 cells reexpressing SHOC2 S2G had modestly lower phosphorylated S365-BRAF and S259-CRAF levels and modestly higher phosphorylated MEK (see 176872) and RSK (see 601684) levels compared to cells expressing wildtype SHOC2, which the authors noted was consistent with RASopathy gain-of-function mutations being only weakly activating and ERK pathway activation by such mutants being difficult to detect in many experimental systems. Young et al. (2018) concluded that the recurrent S2G variant is a gain-of-function mutant that upregulates the ERK pathway during development by selectively promoting phosphatase complex formation with MRAS and PP1. (less)
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001967844.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
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Pathogenic
(Jul 25, 2024)
|
no assertion criteria provided
Method: clinical testing
|
SHOC2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005350870.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The SHOC2 c.4A>G variant is predicted to result in the amino acid substitution p.Ser2Gly. This variant was initially identified in four unrelated individuals with Noonan-like … (more)
The SHOC2 c.4A>G variant is predicted to result in the amino acid substitution p.Ser2Gly. This variant was initially identified in four unrelated individuals with Noonan-like syndrome, three of which were confirmed to be de novo events (Cordeddu et al. 2009. PubMed ID: 19684605), and has since been repeatedly documented as pathogenic in multiple unrelated individuals (Cordeddu et al. 2009. PubMed ID: 19684605; Hoban et al. 2012. PubMed ID: 22528146; Bessis et al. 2019. PubMed ID: 30417923; Leach et al. 2019. PubMed ID: 29907801). Functional studies found that this variant results in aberrant targeting of SHOC2 protein to the plasma membrane, impaired translocation to the nucleus upon growth factor stimulation, and enhanced MAPK activation in a cell type specific manner (Cordeddu et al. 2009. PubMed ID: 19684605). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic by multiple labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). This variant is interpreted as pathogenic. (less)
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|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Rasopathy
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000196678.1
First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015 |
Comment:
Variant classified using ACMG guidelines
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001959945.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
Noonan-like syndrome with loose anagen hair
Affected status: not provided
Allele origin:
germline
|
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)
Accession: SCV000143830.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
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Comment:
Comment:
The p.Ser2Gly variant in SHOC2 is an established pathogenic variant for Noonan s yndrome with loose anagen hair. The variant was identified in >40 affected indiv iduals across multiple studies and in multiple cases was shown to be de novo (Co rdeddu 2009, Komatsuzaki 2010, Gripp 2013, LMM data). It has not been identified large population studies. In vitro functional studies provide some evidence tha t the p.Ser2Gly variant impacts protein function (Cordeddu 2009). In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner.
Comment:
This variant has been previously reported as a de novo change in multiple unrelated patients with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 25331583). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). It is present in one heterozygote in the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, this variant is classified as pathogenic.
Comment:
Variant summary: SHOC2 c.4A>G (p.Ser2Gly) results in a non-conservative amino acid change in the encoded protein sequence, located in the N-terminal region. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248040 control chromosomes. The variant has been reported in literature as one of the most recurrent mutations found in patients with NS or NS-related disorders. It is predominantly found in patients with Noonan-like syndrome with loose anagen hair. The variant was proven to be de novo in multiple patients strongly supporting its pathogenicity. From functional studies this variant was found to introduce an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2-S2G in vitro enhanced MAPK activation in a cell type specific fashion. Induction of SHOC2-S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype associated with aberrant signaling (Cordeddu_2009). In other functional study, the SHOC2-S2G mutant did not rescue ERK1/2 activation in Shoc2-depleted cells and the mutant was not located in late endosomes, however it was present on the plasma membrane and early endosomes (Galperin_2012). 13 clinical diagnostic laboratories (including one expert panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP2,PP3,PP4,PP5.
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 22528146, 21548061, 23918763, 19684605, 25563136, 24458587, PS2, PS4). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19684605, PS3). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000319, PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2 of the SHOC2 protein (p.Ser2Gly). This variant is present in population databases (rs267607048, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 20882035, 22995099, 23918763, 25123707, 25331583). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6821). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SHOC2 function (PMID: 19684605, 22606262). For these reasons, this variant has been classified as Pathogenic.
Comment:
PS2, PS3, PS4, PM6_Strong, PM1, PP2
Comment:
PS2, PM2, PP3, PP5
Comment:
PS2, PS4, PM2
Comment:
ACMG classification criteria: PS2 very strong, PS3 moderate, PS4 moderate, PM2 moderate, PP2 supporting
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome-like with loose anagen hair (MIM#607721). Missense variants in this gene result in enhanced MAPK activation (OMIM, PMID: 19684605). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and is observed in de novo patients with RASopathy (ClinVar, PMID: 25331583). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have demonstrated this variant causes impaired nuclear translocation and MAPK activation (PMID: 19684605). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 19684605, 25846317, 25331583, 25123707). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 19684605, 22606262).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
Located in the critical functional domain S2 and inhibits SHOC2 function by impairing proper cellular localization of the protein (Galperin et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25858597, 22419608, 26350204, 24803665, 31501239, 19684605, 22606262, 25846317, 25563136, 21548061, 24033266, 25326637, 24458596, 24458587, 25331583, 23918763, 25123707, 26096762, 22528146, 26607044, 26519477, 20882035, 22995099, 28680615, 28554332, 24124081, 29737035, 29948256, 30732632, 30240112, 30417923, 30050098, 29907801, 31219622, 30962759, 31584751, 31628766, 31019026, 32005694, 33318624, 34008892, 33300679, 33502061, 32978145, 33240318, 32870709, 34006472, 31785789)
Comment:
The missense c.4A>G(p.Ser2Gly) variant in SHOC2 gene has been reported previously in individual(s) affected with Noonan syndrome with loose anagen hair (Gripp KW, et. al., 2013; Choi JH, et. al., 2015). Functional studies indicate that this variant has a damaging effect on the gene or the gene product (Cordeddu V, et. al., 2009). The p.Ser2Gly variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been submitted to ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Ser2Gly in SHOC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 2 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
The SHOC2 c.4A>G; p.Ser2Gly variant (rs267607048) has been reported in multiple individuals diagnosed with Noonan-like syndrome with loose anagen hair, and often identified as a de novo alteration (Cordeddu 2009, Komatsuzaki 2010, Ekvall 2011, Gripp 2013, Baldassare 2014). Functional characterization of the p.Ser2Gly protein indicates enhanced myristoylation, and aberrant targeting of the SHOC2 to the cell membrane in the absence of growth factor signaling (Cordeddu 2009). This results in an increase in basal and growth-factor stimulated ERK phosphorylation (Cordeddu 2009), consistent with the established disease mechanisms. The variant is classified as pathogenic by many sources in the ClinVar database (Variation ID: 6821) is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is classified as pathogenic. References: Baldassarre G et al. Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation. Am J Med Genet A. 2014 Dec;164A(12):3120-5. PMID: 25331583. Cordeddu V et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009 Sep;41(9):1022-6. PMID: 19684605. Ekvall S et al. Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. Am J Med Genet A. 2011 Jun;155A(6):1217-24. PMID: 21548061. Gripp KW et al. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. Am J Med Genet A. 2013 Oct;161A(10):2420-30. PMID: 23918763. Komatsuzaki S et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 2010 Dec;55(12):801-9. PMID: 20882035.
Comment:
The SHOC2 c.4A>G variant is predicted to result in the amino acid substitution p.Ser2Gly. This variant was initially identified in four unrelated individuals with Noonan-like syndrome, three of which were confirmed to be de novo events (Cordeddu et al. 2009. PubMed ID: 19684605), and has since been repeatedly documented as pathogenic in multiple unrelated individuals (Cordeddu et al. 2009. PubMed ID: 19684605; Hoban et al. 2012. PubMed ID: 22528146; Bessis et al. 2019. PubMed ID: 30417923; Leach et al. 2019. PubMed ID: 29907801). Functional studies found that this variant results in aberrant targeting of SHOC2 protein to the plasma membrane, impaired translocation to the nucleus upon growth factor stimulation, and enhanced MAPK activation in a cell type specific manner (Cordeddu et al. 2009. PubMed ID: 19684605). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic by multiple labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). This variant is interpreted as pathogenic.
Comment:
Variant classified using ACMG guidelines
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.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID: 25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 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). 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): PS2_VeryStrong, PS3, PS4, PM2, PP2.
Comment:
The p.Ser2Gly variant in SHOC2 is an established pathogenic variant for Noonan s yndrome with loose anagen hair. The variant was identified in >40 affected indiv iduals across multiple studies and in multiple cases was shown to be de novo (Co rdeddu 2009, Komatsuzaki 2010, Gripp 2013, LMM data). It has not been identified large population studies. In vitro functional studies provide some evidence tha t the p.Ser2Gly variant impacts protein function (Cordeddu 2009). In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner.
Comment:
This variant has been previously reported as a de novo change in multiple unrelated patients with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 25331583). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). It is present in one heterozygote in the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, this variant is classified as pathogenic.
Comment:
Variant summary: SHOC2 c.4A>G (p.Ser2Gly) results in a non-conservative amino acid change in the encoded protein sequence, located in the N-terminal region. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248040 control chromosomes. The variant has been reported in literature as one of the most recurrent mutations found in patients with NS or NS-related disorders. It is predominantly found in patients with Noonan-like syndrome with loose anagen hair. The variant was proven to be de novo in multiple patients strongly supporting its pathogenicity. From functional studies this variant was found to introduce an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2-S2G in vitro enhanced MAPK activation in a cell type specific fashion. Induction of SHOC2-S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype associated with aberrant signaling (Cordeddu_2009). In other functional study, the SHOC2-S2G mutant did not rescue ERK1/2 activation in Shoc2-depleted cells and the mutant was not located in late endosomes, however it was present on the plasma membrane and early endosomes (Galperin_2012). 13 clinical diagnostic laboratories (including one expert panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP2,PP3,PP4,PP5.
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 22528146, 21548061, 23918763, 19684605, 25563136, 24458587, PS2, PS4). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19684605, PS3). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000319, PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2 of the SHOC2 protein (p.Ser2Gly). This variant is present in population databases (rs267607048, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 20882035, 22995099, 23918763, 25123707, 25331583). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6821). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SHOC2 function (PMID: 19684605, 22606262). For these reasons, this variant has been classified as Pathogenic.
Comment:
PS2, PS3, PS4, PM6_Strong, PM1, PP2
Comment:
PS2, PM2, PP3, PP5
Comment:
PS2, PS4, PM2
Comment:
ACMG classification criteria: PS2 very strong, PS3 moderate, PS4 moderate, PM2 moderate, PP2 supporting
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome-like with loose anagen hair (MIM#607721). Missense variants in this gene result in enhanced MAPK activation (OMIM, PMID: 19684605). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and is observed in de novo patients with RASopathy (ClinVar, PMID: 25331583). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have demonstrated this variant causes impaired nuclear translocation and MAPK activation (PMID: 19684605). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 19684605, 25846317, 25331583, 25123707). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 19684605, 22606262).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
Located in the critical functional domain S2 and inhibits SHOC2 function by impairing proper cellular localization of the protein (Galperin et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25858597, 22419608, 26350204, 24803665, 31501239, 19684605, 22606262, 25846317, 25563136, 21548061, 24033266, 25326637, 24458596, 24458587, 25331583, 23918763, 25123707, 26096762, 22528146, 26607044, 26519477, 20882035, 22995099, 28680615, 28554332, 24124081, 29737035, 29948256, 30732632, 30240112, 30417923, 30050098, 29907801, 31219622, 30962759, 31584751, 31628766, 31019026, 32005694, 33318624, 34008892, 33300679, 33502061, 32978145, 33240318, 32870709, 34006472, 31785789)
Comment:
The missense c.4A>G(p.Ser2Gly) variant in SHOC2 gene has been reported previously in individual(s) affected with Noonan syndrome with loose anagen hair (Gripp KW, et. al., 2013; Choi JH, et. al., 2015). Functional studies indicate that this variant has a damaging effect on the gene or the gene product (Cordeddu V, et. al., 2009). The p.Ser2Gly variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been submitted to ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Ser2Gly in SHOC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 2 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
The SHOC2 c.4A>G; p.Ser2Gly variant (rs267607048) has been reported in multiple individuals diagnosed with Noonan-like syndrome with loose anagen hair, and often identified as a de novo alteration (Cordeddu 2009, Komatsuzaki 2010, Ekvall 2011, Gripp 2013, Baldassare 2014). Functional characterization of the p.Ser2Gly protein indicates enhanced myristoylation, and aberrant targeting of the SHOC2 to the cell membrane in the absence of growth factor signaling (Cordeddu 2009). This results in an increase in basal and growth-factor stimulated ERK phosphorylation (Cordeddu 2009), consistent with the established disease mechanisms. The variant is classified as pathogenic by many sources in the ClinVar database (Variation ID: 6821) is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is classified as pathogenic. References: Baldassarre G et al. Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation. Am J Med Genet A. 2014 Dec;164A(12):3120-5. PMID: 25331583. Cordeddu V et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009 Sep;41(9):1022-6. PMID: 19684605. Ekvall S et al. Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. Am J Med Genet A. 2011 Jun;155A(6):1217-24. PMID: 21548061. Gripp KW et al. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. Am J Med Genet A. 2013 Oct;161A(10):2420-30. PMID: 23918763. Komatsuzaki S et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 2010 Dec;55(12):801-9. PMID: 20882035.
Comment:
The SHOC2 c.4A>G variant is predicted to result in the amino acid substitution p.Ser2Gly. This variant was initially identified in four unrelated individuals with Noonan-like syndrome, three of which were confirmed to be de novo events (Cordeddu et al. 2009. PubMed ID: 19684605), and has since been repeatedly documented as pathogenic in multiple unrelated individuals (Cordeddu et al. 2009. PubMed ID: 19684605; Hoban et al. 2012. PubMed ID: 22528146; Bessis et al. 2019. PubMed ID: 30417923; Leach et al. 2019. PubMed ID: 29907801). Functional studies found that this variant results in aberrant targeting of SHOC2 protein to the plasma membrane, impaired translocation to the nucleus upon growth factor stimulation, and enhanced MAPK activation in a cell type specific manner (Cordeddu et al. 2009. PubMed ID: 19684605). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic by multiple labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). This variant is interpreted as pathogenic.
Comment:
Variant classified using ACMG guidelines
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis. | Young LC | Proceedings of the National Academy of Sciences of the United States of America | 2018 | PMID: 30348783 |
| SHOC2 subcellular shuttling requires the KEKE motif-rich region and N-terminal leucine-rich repeat domain and impacts on ERK signalling. | Motta M | Human molecular genetics | 2016 | PMID: 27466182 |
| Spatial control of Shoc2-scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5. | Jang ER | Journal of cell science | 2015 | PMID: 26519477 |
| Moyamoya syndrome in a patient with Noonan-like syndrome with loose anagen hair. | Choi JH | Pediatric neurology | 2015 | PMID: 25563136 |
| Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation. | Baldassarre G | American journal of medical genetics. Part A | 2014 | PMID: 25331583 |
| Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: clinical evidence of crosslink between FGFR and RAS signaling pathways. | Takenouchi T | American journal of medical genetics. Part A | 2014 | PMID: 25123707 |
| Coarctation of the aorta in Noonan-like syndrome with loose anagen hair. | Zmolikova M | American journal of medical genetics. Part A | 2014 | PMID: 24458596 |
| Hydrops fetalis in a preterm newborn heterozygous for the c.4A>G SHOC2 mutation. | Gargano G | American journal of medical genetics. Part A | 2014 | PMID: 24458587 |
| Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. | Gripp KW | American journal of medical genetics. Part A | 2013 | PMID: 23918763 |
| Noonan syndrome: comparing mutation-positive with mutation-negative dutch patients. | Croonen EA | Molecular syndromology | 2013 | PMID: 23885229 |
| Are RASopathies new monogenic predisposing conditions to the development of systemic lupus erythematosus? Case report and systematic review of the literature. | Bader-Meunier B | Seminars in arthritis and rheumatism | 2013 | PMID: 23786871 |
| Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome. | Timeus F | Oncology reports | 2013 | PMID: 23756559 |
| Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation. | Capalbo D | Italian journal of pediatrics | 2012 | PMID: 22995099 |
| Shoc2 is targeted to late endosomes and required for Erk1/2 activation in EGF-stimulated cells. | Galperin E | PloS one | 2012 | PMID: 22606262 |
| Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant. | Hoban R | American journal of medical genetics. Part A | 2012 | PMID: 22528146 |
| Noonan-like syndrome with loose anagen hair associated with growth hormone insensitivity and atypical neurological manifestations. | Capalbo D | American journal of medical genetics. Part A | 2012 | PMID: 22419608 |
| Transcriptional hallmarks of Noonan syndrome and Noonan-like syndrome with loose anagen hair. | Ferrero GB | Human mutation | 2012 | PMID: 22253195 |
| Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. | Lee BH | The Journal of pediatrics | 2011 | PMID: 21784453 |
| Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. | Ekvall S | American journal of medical genetics. Part A | 2011 | PMID: 21548061 |
| Noonan syndrome and clinically related disorders. | Tartaglia M | Best practice & research. Clinical endocrinology & metabolism | 2011 | PMID: 21396583 |
| Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. | Komatsuzaki S | Journal of human genetics | 2010 | PMID: 20882035 |
| Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. | Cordeddu V | Nature genetics | 2009 | PMID: 19684605 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SHOC2 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/39b0e509-abdb-415d-87bd-98b7310bb1c0 | - | - | - | - |
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Text-mined citations for rs267607048 ...
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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.