Submissions for variant NM_024422.6(DSC2):c.1914G>C (p.Gln638His)

gnomAD frequency: 0.00036  dbSNP: rs147742157

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172525	SCV000050857	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039414	SCV000063098	uncertain significance	not specified	2015-12-10	criteria provided, single submitter	clinical testing	The p.Gln638His variant in DSC2 has been reported in at least 4 individuals with a range of phenotypes (DCM, ARVD/C, HCM) (Elliot 2010, Cox 2011, LMM unpublishe d data). This variant has been identified in 0.1% (11/16342) of South Asian chr omosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org; db SNP rs147742157) and once in another control population in the literature (Den H aan 2009). Computational prediction tools and conservation analysis suggest that the p.Gln638His variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical signif icance of the p.Gln638His variant is uncertain.
GeneDx	RCV000172525	SCV000233435	likely benign	not provided	2020-11-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21606396, 23861362, 20031617, 20716751, 20152563, 20857253, 20829228)
Invitae	RCV001081432	SCV000551493	benign	Arrhythmogenic right ventricular dysplasia 11	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172525	SCV000704878	uncertain significance	not provided	2017-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776094	SCV000910885	benign	Cardiomyopathy	2018-06-05	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852737	SCV000995452	likely benign	Hypertrophic cardiomyopathy	2018-03-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001081432	SCV001288105	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2018-02-05	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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	RCV000776094	SCV001334025	benign	Cardiomyopathy	2017-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039414	SCV001363402	benign	not specified	2020-08-17	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.1914G>C (p.Gln638His) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 252554 control chromosomes, predominantly at a frequency of 0.00069 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1914G>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy (DCM) and Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC, Elliott_2010, Xu_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=5). Based on the evidence outlined above, the variant was re-classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000172525	SCV002063676	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	DSC2: BP4
Ambry Genetics	RCV002408524	SCV002720005	likely benign	Cardiovascular phenotype	2018-05-22	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.
PreventionGenetics, part of Exact Sciences	RCV003934941	SCV004752280	likely benign	DSC2-related disorder	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Genetics, Academic Medical Center	RCV000172525	SCV001924264	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172525	SCV001930070	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172525	SCV001951362	likely benign	not provided		no assertion criteria provided	clinical testing