Submissions for variant NM_024422.6(DSC2):c.2162C>A (p.Thr721Lys)

dbSNP: rs759513934

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770530	SCV000901977	uncertain significance	Cardiomyopathy	2015-09-11	criteria provided, single submitter	clinical testing
Invitae	RCV000807390	SCV000947438	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2020-12-23	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DSC2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 721 of the DSC2 protein (p.Thr721Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine.
Illumina Laboratory Services, Illumina	RCV000807390	SCV001285790	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000770530	SCV001340080	uncertain significance	Cardiomyopathy	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 721 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194114	SCV001363400	uncertain significance	not specified	2019-11-04	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.2162C>A (p.Thr721Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251264 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2162C>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000807390	SCV003829125	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2019-12-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999945	SCV004816090	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 721 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 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	RCV004027226	SCV005028745	uncertain significance	Cardiovascular phenotype	2023-12-11	criteria provided, single submitter	clinical testing	The p.T721K variant (also known as c.2162C>A), located in coding exon 14 of the DSC2 gene, results from a C to A substitution at nucleotide position 2162. The threonine at codon 721 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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.