Submissions for variant NM_024422.6(DSC2):c.82G>T (p.Ala28Ser)

gnomAD frequency: 0.00009  dbSNP: rs139979318

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000246853	SCV000317822	likely benign	Cardiovascular phenotype	2021-08-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622276	SCV000740323	uncertain significance	Primary familial dilated cardiomyopathy	2017-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV001045823	SCV001209697	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 28 of the DSC2 protein (p.Ala28Ser). This variant is present in population databases (rs139979318, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234988). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001176601	SCV001340629	uncertain significance	Cardiomyopathy	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 28 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. This variant has been identified in 5/280590 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV002051829	SCV002319159	uncertain significance	not provided	2022-03-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223928	SCV000280080	uncertain significance	not specified	2013-01-07	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we characterize this variant as a variant of uncertain significance. This variant has not been previously reported as a disease-causing mutation according to searches of PubMed and Google; it is present, however, in an African American population dataset. Variants in this gene can cause arrhythmogenic right ventricular cardiomyopathy (ARVC). This is a non-conservative amino acid change from a nonpolar alanine to a neutral, polar serine. It has a Grantham score of 99. The alanine at codon 28 is not well conserved across 30 vertebrate species examined (it is a serine in opossum, as in this patient, and a threonine in dog, kangaroo rat, and pika). In silico analysis with PolyPhen-2 (humVAR) predicts the variant to be “benign” with a score of 0.078; SIFT predicts it to be “tolerated” with a score of 0.830. In total this specific variant has been seen in 3 out of ~2500 African-American individuals from publicly available population datasets. It is present in 3/2203 African-American individuals in the NHLBI Exome Sequencing Project dataset, for an allele frequency of 0.07%. It was not present in 4300 European American individuals. This gives it an overall allele frequency in the ESP of 0.02%. It is present in dbSNP as rs139979318, submitted by the ESP. It is not present in 1000 genomes. (1000 genomes phase 1 is made up of 1092 individuals of various races, 246 of them with African or African-American ancestry). Presence of a variant among individuals in the general population cannot definitively rule it out as the cause of disease, as even gold-standard pathogenic cardiomyopathy variants have been found in population datasets (Pan et al. 2012).