Submissions for variant NM_024422.6(DSC2):c.1694T>G (p.Ile565Ser)

dbSNP: rs1986963426

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001071571	SCV001236880	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with serine at codon 565 of the DSC2 protein (p.Ile565Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553573	SCV001774473	uncertain significance	not specified	2021-07-12	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.1694T>G (p.Ile565Ser) results in a non-conservative amino acid change located in the 4th cadherin repeat (IPR002126) of the encoded protein. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250746 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.1694T>G in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV001071571	SCV002815324	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-10-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000203	SCV004817216	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with serine at codon 565 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 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.