Submissions for variant NM_024422.6(DSC2):c.1069C>T (p.Arg357Cys)

gnomAD frequency: 0.00005  dbSNP: rs879255385

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239125	SCV000297174	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-07-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589114	SCV000699492	uncertain significance	not provided	2016-08-22	criteria provided, single submitter	clinical testing	Variant summary: The DSC2 c.1069C>T (p.Arg357Cys) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 118790 control chromosomes. In addition, one clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV001302059	SCV001491249	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 357 of the DSC2 protein (p.Arg357Cys). This variant is present in population databases (no rsID available, gnomAD 0.008%). 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: 252639). 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.
GeneDx	RCV000589114	SCV001778997	uncertain significance	not provided	2021-05-06	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 252639; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Ambry Genetics	RCV002411107	SCV002721516	uncertain significance	Cardiovascular phenotype	2019-09-30	criteria provided, single submitter	clinical testing	The p.R357C variant (also known as c.1069C>T), located in coding exon 8 of the DSC2 gene, results from a C to T substitution at nucleotide position 1069. The arginine at codon 357 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV001302059	SCV002780351	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-11-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532070	SCV004363101	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 357 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 cardiovascular disorders in the literature. This variant has been identified in 3/282360 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.