Submissions for variant NM_024422.6(DSC2):c.907G>A (p.Val303Met)

gnomAD frequency: 0.00021  dbSNP: rs145560678

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039445	SCV000063129	likely benign	not specified	2016-11-15	criteria provided, single submitter	clinical testing	p.Val303Met in exon 7 of DSC2: This variant has been identified in 0.7% (120/165 12) of South Asian chromosomes, including 1 homozygote, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145560678). This vari ant was previously reported in 1 individual with DCM (Garcia-Pavia 2011). Howeve r, given the high frequency of this variant in the general population, it is not expected to have clinical significance.
GeneDx	RCV000039445	SCV000233423	benign	not specified	2017-02-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227622	SCV000290740	benign	Arrhythmogenic right ventricular dysplasia 11	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621747	SCV000736344	likely benign	Cardiovascular phenotype	2018-09-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000227622	SCV000743496	likely benign	Arrhythmogenic right ventricular dysplasia 11	2017-07-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771128	SCV000902897	likely benign	Cardiomyopathy	2018-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039445	SCV000919275	likely benign	not specified	2020-11-02	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.907G>A (p.Val303Met) results in a conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 252686 control chromosomes, predominantly at a frequency of 0.0068 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 680-fold the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.907G>A has been reported in the literature in at least one individual affected with cardiomyopathy (e.g. Garcia-Pavia_2011), but also in healthy controls (e.g. Kapplinger_2011). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as benign/likely benign (n=8) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000858410	SCV001151502	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	DSC2: BP4
Illumina Laboratory Services, Illumina	RCV000227622	SCV001281728	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771128	SCV001334028	benign	Cardiomyopathy	2018-03-20	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000227622	SCV001984560	benign	Arrhythmogenic right ventricular dysplasia 11	2020-01-08	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000039445	SCV001921757	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000858410	SCV001954595	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000858410	SCV001964350	likely benign	not provided		no assertion criteria provided	clinical testing