ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.857G>T (p.Gly286Val) (rs199682735)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618085 SCV000737023 uncertain significance Cardiovascular phenotype 2017-04-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171893 SCV000054843 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171893 SCV000233402 uncertain significance not provided 2017-02-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSC2 gene. The G286V variant has been reported in one patient with HCM (Lopes et al., 2015); however, additional clinical and segregation information were not included. Additionally, this variant was also reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013). The G286V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, the G286V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Illumina Clinical Services Laboratory,Illumina RCV000320626 SCV000408102 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000705660 SCV000834668 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 286 of the DSC2 protein (p.Gly286Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs199682735, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 191623). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000214695 SCV000271710 uncertain significance not specified 2015-06-03 criteria provided, single submitter clinical testing The p.Gly286Val variant in DSC2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 3/11544 Latino chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs19 9682735). Computational prediction tools and conservation analysis do not provid e strong support for or against an impact to the protein. In summary, the clinic al significance of the p.Gly286Val variant is uncertain.

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