Submissions for variant NM_024422.6(DSC2):c.965A>G (p.Lys322Arg)

gnomAD frequency: 0.00002  dbSNP: rs1157312147

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001189571	SCV001356882	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 322 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001207317	SCV001378662	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with arginine at codon 322 of the DSC2 protein (p.Lys322Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	RCV003163469	SCV003853616	uncertain significance	Cardiovascular phenotype	2023-01-01	criteria provided, single submitter	clinical testing	The p.K322R variant (also known as c.965A>G), located in coding exon 8 of the DSC2 gene, results from an A to G substitution at nucleotide position 965. The lysine at codon 322 is replaced by arginine, an amino acid with highly 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.
All of Us Research Program, National Institutes of Health	RCV004010368	SCV004816190	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 322 of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant 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). 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.