Submissions for variant NM_024422.6(DSC2):c.2591C>T (p.Ser864Leu)

gnomAD frequency: 0.00004  dbSNP: rs202031070

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000644641	SCV000766344	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 864 of the DSC2 protein (p.Ser864Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 536272). 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 disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV001805776	SCV002051922	uncertain significance	Cardiomyopathy	2022-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 864 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001805776	SCV004240492	uncertain significance	Cardiomyopathy	2023-03-22	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001092831	SCV001922781	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001092831	SCV001951069	uncertain significance	not provided		no assertion criteria provided	clinical testing