This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
ClinVar Genomic variation as it relates to human health
NM_207122.2(EXT2):c.1022C>T (p.Pro341Leu)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)
Uncertain significance(4); Likely benign(1)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_207122.2(EXT2):c.1022C>T (p.Pro341Leu)
Variation ID: 134215 Accession: VCV000134215.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p11.2 11: 44126898 (GRCh38) [ NCBI UCSC ] 11: 44148448 (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 Jun 9, 2014 Feb 20, 2024 Dec 17, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_207122.2:c.1022C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_997005.1:p.Pro341Leu missense NM_000401.3:c.1121C>T NP_000392.3:p.Pro374Leu missense NM_001178083.3:c.1022C>T NP_001171554.1:p.Pro341Leu missense NM_001389628.1:c.1022C>T NP_001376557.1:p.Pro341Leu missense NM_001389630.1:c.1022C>T NP_001376559.1:p.Pro341Leu missense NC_000011.10:g.44126898C>T NC_000011.9:g.44148448C>T NG_007560.1:g.36350C>T LRG_494:g.36350C>T LRG_494t1:c.1121C>T LRG_494p1:p.Pro374Leu LRG_494t2:c.1022C>T LRG_494p2:p.Pro341Leu - Protein change
- P341L, P374L
- Other names
- -
- Canonical SPDI
- NC_000011.10:44126897:C:T
-
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) 0.00027
The Genome Aggregation Database (gnomAD), exomes 0.00028
Trans-Omics for Precision Medicine (TOPMed) 0.00037
The Genome Aggregation Database (gnomAD) 0.00044
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092
- 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. |
|||
| EXT2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
766 | 869 | |
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. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
Sep 19, 2013 | RCV000120888.4 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763739.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 18, 2022 | RCV000766600.5 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Dec 17, 2023 | RCV000795903.20 |
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Exostoses, multiple, type 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000371844.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
|
|
|
Uncertain significance
(Feb 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000576979.7
First in ClinVar: Jun 09, 2014 Last updated: Mar 04, 2023 |
Comment:
Has not been previously published as pathogenic or benign in association with EXT2-related disorders to our knowledge; In silico analysis supports that this missense variant … (more)
Has not been previously published as pathogenic or benign in association with EXT2-related disorders to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28384719, 27535533, 28166811, 24728327) (less)
|
|
|
Uncertain significance
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Exostoses, multiple, type 2
Seizures-scoliosis-macrocephaly syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894624.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Uncertain significance
(Oct 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Exostoses, multiple, type 2
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002525986.4
First in ClinVar: Jun 16, 2022 Last updated: Dec 02, 2023 |
Comment:
The EXT2 c.1121C>T (p.Pro374Leu) missense change has a maximum subpopulation frequency of 0.050% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious … (more)
The EXT2 c.1121C>T (p.Pro374Leu) missense change has a maximum subpopulation frequency of 0.050% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary multiple exostoses. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
|
|
|
Uncertain significance
(Dec 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Exostoses, multiple, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000935384.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 341 of the EXT2 protein (p.Pro341Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 341 of the EXT2 protein (p.Pro341Leu). This variant is present in population databases (rs141035971, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134215). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXT2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000085056.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Multiple exostoses type 2
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV001423440.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Uncertain significance and reported on 04-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpretted as Uncertain significance and reported on 04-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Diabetes mellitus type 2 (present) , Diabetes mellitus type 1 (present) , Delayed puberty (present) , Myopia (disease) (present) , Movement disorder (present) , Joint … (more)
Diabetes mellitus type 2 (present) , Diabetes mellitus type 1 (present) , Delayed puberty (present) , Myopia (disease) (present) , Movement disorder (present) , Joint hypermobility (present) , Arrhythmia (present) , Abnormal EKG (present) , Hypertensive disorder (present) , Hypercholesterolemia (present) , Abnormality of esophagus morphology (present) , Abnormality of the liver (present) , Abnormality of the intestine (present) , Abnormality of the bladder (present) , Autoimmunity (present) , Abnormal inflammatory response (present) , Gingivitis (present) (less)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-04-29
Testing laboratory interpretation: Uncertain significance
|
Comment:
Comment:
Has not been previously published as pathogenic or benign in association with EXT2-related disorders to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28384719, 27535533, 28166811, 24728327)
Comment:
The EXT2 c.1121C>T (p.Pro374Leu) missense change has a maximum subpopulation frequency of 0.050% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary multiple exostoses. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 341 of the EXT2 protein (p.Pro341Leu). This variant is present in population databases (rs141035971, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134215). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXT2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Variant interpretted as Uncertain significance and reported on 04-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Comment:
Has not been previously published as pathogenic or benign in association with EXT2-related disorders to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28384719, 27535533, 28166811, 24728327)
Comment:
The EXT2 c.1121C>T (p.Pro374Leu) missense change has a maximum subpopulation frequency of 0.050% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary multiple exostoses. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 341 of the EXT2 protein (p.Pro341Leu). This variant is present in population databases (rs141035971, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134215). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXT2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Variant interpretted as Uncertain significance and reported on 04-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs141035971 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.