Submissions for variant NM_024422.6(DSC2):c.1469G>A (p.Ser490Asn)

gnomAD frequency: 0.00001  dbSNP: rs780446276

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588208	SCV000699494	uncertain significance	not specified	2021-04-20	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.1469G>A (p.Ser490Asn) results in a conservative amino acid change located in one of the cadherin repeats (IPR002126) in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 364604 control chromosomes in the gnomAD database (v2.1 and v3 dataset). 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.1469G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000622716	SCV000742841	uncertain significance	Inborn genetic diseases	2017-08-10	criteria provided, single submitter	clinical testing
Invitae	RCV001299228	SCV001488311	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine with asparagine at codon 490 of the DSC2 protein (p.Ser490Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs780446276, ExAC 0.01%). 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: 496458). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV002395511	SCV002701586	uncertain significance	Cardiovascular phenotype	2021-05-13	criteria provided, single submitter	clinical testing	The p.S490N variant (also known as c.1469G>A), located in coding exon 10 of the DSC2 gene, results from a G to A substitution at nucleotide position 1469. The serine at codon 490 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is poorly 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	RCV001299228	SCV002779122	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-09-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532182	SCV004363092	uncertain significance	Cardiomyopathy	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 490 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 DSC2-related disorders in the literature. This variant has been identified in 1/251272 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.