Submissions for variant NM_024422.6(DSC2):c.2636A>G (p.Asp879Gly)

gnomAD frequency: 0.00079  dbSNP: rs143342988

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001701546	SCV000233446	likely benign	not provided	2020-12-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21636032, 25516398, 29802319)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000181169	SCV000270163	likely benign	not specified	2015-05-16	criteria provided, single submitter	clinical testing	p.Asp879Gly in exon 16 of DSC2: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (35/10398) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs143342988).
Invitae	RCV000475212	SCV000561697	likely benign	Arrhythmogenic right ventricular dysplasia 11	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619644	SCV000734914	likely benign	Cardiovascular phenotype	2019-01-21	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.
Color Diagnostics, LLC DBA Color Health	RCV001184989	SCV001351102	likely benign	Cardiomyopathy	2018-12-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181169	SCV001554536	benign	not specified	2021-03-25	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.2636A>G (p.Asp879Gly) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain (IPR000233) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 252158 control chromosomes. The observed variant frequency is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2636A>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus of likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV003917691	SCV004732579	likely benign	DSC2-related disorder	2023-05-21	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).
All of Us Research Program, National Institutes of Health	RCV003996604	SCV004823877	likely benign	Familial isolated arrhythmogenic right ventricular dysplasia	2024-02-05	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000181169	SCV001925066	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701546	SCV001928200	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701546	SCV001980465	likely benign	not provided		no assertion criteria provided	clinical testing