Submissions for variant NM_024422.6(DSC2):c.1788G>A (p.Ala596=)

gnomAD frequency: 0.00013  dbSNP: rs146161960

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000554581	SCV000408099	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.
Invitae	RCV000554581	SCV000644996	likely benign	Arrhythmogenic right ventricular dysplasia 11	2023-11-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001718682	SCV000723443	likely benign	not provided	2020-12-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171302	SCV001334026	benign	Cardiomyopathy	2017-12-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171302	SCV001347323	likely benign	Cardiomyopathy	2018-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000606828	SCV001361048	benign	not specified	2019-01-28	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.1788G>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 0.00012 in 276856 control chromosomes (gnomAD). The observed variant frequency is approximately 5 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 benign. To our knowledge, no occurrence of c.1788G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as likely benign (2x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000606828	SCV001365490	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Ala596Ala in Exon 12 of DSC2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence. It has been identified in 1/7020 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs146161960).
Ambry Genetics	RCV002402047	SCV002711398	likely benign	Cardiovascular phenotype	2020-06-21	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.
All of Us Research Program, National Institutes of Health	RCV003995851	SCV004816121	likely benign	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-13	criteria provided, single submitter	clinical testing