ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.841A>G (p.Lys281Glu)

gnomAD frequency: 0.00003  dbSNP: rs373697870
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002001205 SCV002269320 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2021-08-18 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 281 of the DSC2 protein (p.Lys281Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs373697870, ExAC 0.01%). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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 RCV002407243 SCV002675817 likely benign Cardiovascular phenotype 2024-03-12 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health RCV004011065 SCV004831437 uncertain significance Familial isolated arrhythmogenic right ventricular dysplasia 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 281 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 2/282784 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.

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