ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1766T>C (p.Met589Thr) (rs201856473)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619775 SCV000734886 uncertain significance Cardiovascular phenotype 2018-02-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000772020 SCV000904976 uncertain significance Cardiomyopathy 2018-04-23 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the extracellular domain 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 the 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 20/276810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000481832 SCV000564947 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSC2 gene. The M589T variant has not been published as pathogenic or been reported as benign to our knowledge. The M589T 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). Additionally, the M589T 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. However, this substitution occurs at a position that is not conserved across species. Moreover, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000467720 SCV000551484 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 589 of the DSC2 protein (p.Met589Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs201856473, ExAC 0.01%). This variant has been reported in the literature in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 410648). 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. 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.
Phosphorus, Inc. RCV000467720 SCV000679937 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-08-01 criteria provided, single submitter clinical testing

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