Submissions for variant NM_024422.6(DSC2):c.4G>A (p.Glu2Lys)

gnomAD frequency: 0.00008  dbSNP: rs762556795

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181170	SCV000233447	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	Reported in one Danish individual fulfilling task force criteria for a diagnosis of ARVC (Christensen et al., 2010); Identified in 15 individuals from a cohort of 30,716 predominantly European individuals undergoing exome sequencing and review of available electronic health records indicated that none of these individuals had a documented diagnosis of ARVC (Haggerty et al., 2017), although specific clinical details and follow-up cardiac evaluations were not reported; Identified in conjunction with additional variants in individuals referred for cardiac genetic testing at GeneDx; segregation data are limited at this time; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23911551, 20864495, 26264440, 28471438, 31402444)
Invitae	RCV000546172	SCV000645018	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2 of the DSC2 protein (p.Glu2Lys). This variant is present in population databases (rs762556795, gnomAD 0.03%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495). ClinVar contains an entry for this variant (Variation ID: 199776). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV000619111	SCV000737951	likely benign	Cardiovascular phenotype	2021-10-04	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	RCV000778023	SCV000914134	uncertain significance	Cardiomyopathy	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2 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 been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26264440). This variant has been identified in 16/149434 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002111	SCV001159958	uncertain significance	not specified	2018-10-05	criteria provided, single submitter	clinical testing	The p.Glu2Lys variant (rs762556795) was reported in one patient with palpitation at 15 years age of onset without a family history (Christensen 2010). This variant is listed in the Genome Aggregation Database (gnomAD) with a population frequency of 0.02 percent in the European Non-Finnish population (identified on 12 out of 56,600 chromosomes) and has been reported to the ClinVar database (Variation ID: 199776). The glutamic acid at the second codon is weakly conserved and before the signal peptide which is cleaved off before insertion into the plasma membrane. Computational analyses of the p.Glu2Lys variant on protein structure and function provide conflicting results (SIFT: damaging, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Glu2Lys variant with certainty.
Illumina Laboratory Services, Illumina	RCV000546172	SCV001285910	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2017-04-27	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.
Fulgent Genetics, Fulgent Genetics	RCV000546172	SCV002790099	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-11-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996605	SCV004819397	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2 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 been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26264440). This variant has been identified in 16/149434 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.