Submissions for variant NM_024422.6(DSC2):c.1971C>A (p.Gly657=)

gnomAD frequency: 0.00001  dbSNP: rs397517396

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039416	SCV000063100	likely benign	not specified	2012-08-22	criteria provided, single submitter	clinical testing	Gly657Gly in exon 13 of DSC2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. Gly657Gly in exon 13 of DSC2 (allele frequenc y = n/a)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039416	SCV000917285	benign	not specified	2018-12-26	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.1971C>A alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.9e-05 in 245192 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.001 in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 100-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 a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.1971C>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV001126574	SCV001285794	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2018-01-13	criteria provided, single submitter	clinical testing	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV001182266	SCV001347659	likely benign	Cardiomyopathy	2018-12-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001311137	SCV001893550	likely benign	not provided	2018-09-14	criteria provided, single submitter	clinical testing
Invitae	RCV001126574	SCV002487272	benign	Arrhythmogenic right ventricular dysplasia 11	2023-11-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996435	SCV004816108	likely benign	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018890	SCV005028744	likely benign	Cardiovascular phenotype	2022-12-23	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.