ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1034T>C (p.Ile345Thr) (rs777688726)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619062 SCV000735575 uncertain significance Cardiovascular phenotype 2016-10-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000226472 SCV000290725 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2015-12-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 345 of the DSC2 protein (p.Ile345Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs777688726, ExAC 0.009%). This variant has been reported in an individual with arrhythmogenic right ventricular cardiomyopathy (PMID: 17963498). This individual's 15 year old daughter also carried this variant but did not show any arrhythmic symptoms at the time of evaluation. 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 disruptive. Experimental studies have shown that this missense change results in mislocalization of the DSC2 protein in cell culture, but the clinical significance of this finding has not been established (PMID: 17963498) . In summary, this is a rare missense change that is predicted to disrupt protein function. While this variant has been reported in the literature in an affected individual, the available evidence is insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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