ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2335G>A (p.Gly779Arg) (rs139290300)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618174 SCV000737962 uncertain significance Cardiovascular phenotype 2017-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171888 SCV000054841 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Color RCV000778022 SCV000914133 uncertain significance Cardiomyopathy 2018-10-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic domain of the DSC2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on 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 been identified in 11/276832 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000171888 SCV000343580 uncertain significance not provided 2016-07-05 criteria provided, single submitter clinical testing
GeneDx RCV000171888 SCV000233441 uncertain significance not provided 2014-06-25 criteria provided, single submitter clinical testing p.Gly779Arg (GGA>AGA): c.2335 G>A in exon 15 of the DSC2 gene (NM_024422.3) A variant of unknown significance has been identified in the DSC2 gene. The G779R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G779R variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The G779R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, mutations in nearby residues have not been reported in association with arrhythmia, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000171888 SCV000699498 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing
Invitae RCV000644646 SCV000766349 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-01-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 779 of the DSC2 protein (p.Gly779Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs139290300, ExAC 0.009%). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 191619). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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.

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