Submissions for variant NM_024422.6(DSC2):c.23G>T (p.Gly8Val)

gnomAD frequency: 0.00009  dbSNP: rs794728063

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181133	SCV000233410	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	Reported in individuals with cardiomyopathy; however, clinical details and segregation studies were not described (Rasmussen et al., 2014; van Lint et al., 2019; Pottinger et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 32009526, 24704780)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769506	SCV000900901	uncertain significance	Cardiomyopathy	2017-10-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769506	SCV000914132	uncertain significance	Cardiomyopathy	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 8 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 identified in an individual with a definite or borderline diagnosis of arrhythmogenic cardiomyopathy (PMID: 24704780). This variant has been identified in 14/152998 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825917	SCV000967402	uncertain significance	not specified	2018-10-10	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Gly8Val varia nt in DSC2 has been reported in 1 individuals with arrhythmogenic cardiomyopathy or borderline arrhythmogenic cardiomyopathy (Rasmussen 2014). It has also been identified in 0.02% (13/57888) of European chromosomes by gnomAD (http://gnomad. broadinstitute.org). Computational prediction tools and conservation analysis su ggest that this variant may not impact the protein, though this information is n ot predictive enough to rule out pathogenicity. In summary, while the clinical s ignificance of the p.Gly8Val variant is uncertain, its frequency suggests that i t is more likely to be benign. ACMG/AMP criteria applied: BP4.
Invitae	RCV001061930	SCV001226694	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 8 of the DSC2 protein (p.Gly8Val). This variant is present in population databases (rs794728063, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy (PMID: 24704780, 32009526). ClinVar contains an entry for this variant (Variation ID: 199758). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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	RCV002444725	SCV002732563	likely benign	Cardiovascular phenotype	2022-12-21	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000181133	SCV004224474	uncertain significance	not provided	2022-04-08	criteria provided, single submitter	clinical testing	BP4
All of Us Research Program, National Institutes of Health	RCV003996595	SCV004819393	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 8 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 identified in an individual with a definite or borderline diagnosis of arrhythmogenic cardiomyopathy (PMID: 24704780). This variant has been identified in 14/152998 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.