Submissions for variant NM_024422.6(DSC2):c.824C>A (p.Thr275Lys)

dbSNP: rs397517404

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039440	SCV000063124	uncertain significance	not specified	2012-02-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Thr275Lys v ariant in DSC2 has been identified by our laboratory in 2 individuals with ARVC from one family who carried a second variant on the other copy of the DSC2 gene. The Thr275Lys variant was also detected in an affected relative and has not bee n identified in large population studies. Of note, another variant at this posit ion, Thr275Met, was reported in 1 individual with ARVC in the homozygous state a nd was demonstrated to impact the maturation and intracellular localization of t he protein (Gehmlich 2011), although these in vitro assays may not accurately re present biological function. Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Thr275Lys variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. Although this data supports that the Thr275Lys var iant may be pathogenic, additional studies are needed to fully assess its clinic al significance.
GeneDx	RCV001762122	SCV001991874	uncertain significance	not provided	2019-04-11	criteria provided, single submitter	clinical testing	Has not been previously reported as pathogenic or benign to our knowledge; A different missense change at this residue (T275M) has been reported in the published literature, as pathogenic in the homozygous state in a patient with ARVC, and the patient's heterozygous children were asymptomatic (Gehmlich et al., 2011); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21062920, 28588093)
Color Diagnostics, LLC DBA Color Health	RCV003531939	SCV004363113	uncertain significance	Cardiomyopathy	2023-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 275 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: 28588093). This variant has not been identified 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.
Ambry Genetics	RCV004018892	SCV004858875	uncertain significance	Cardiovascular phenotype	2022-05-23	criteria provided, single submitter	clinical testing	The c.824C>A (p.T275K) alteration is located in exon 7 (coding exon 7) of the DSC2 gene. This alteration results from a C to A substitution at nucleotide position 824, causing the threonine (T) at amino acid position 275 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.