ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1729A>G (p.Ile577Val) (rs201845641)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171890 SCV000054842 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000039411 SCV000063095 uncertain significance not specified 2014-07-03 criteria provided, single submitter clinical testing The Ile577Val variant in DSC2 has been identified by our laboratory in 2 Caucasi an adults with DCM (including this family), both of whom carried another likely pathogenic variant. This variant has also been identified in 1/8600 European Ame rican chromosomes by the NHLBI Exome Sequencing Project (; dbSNP rs201845641) and was reported in 1/186 controls in an unpublis hed study (ARVD/C Database, Computational predict ion tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical significance of the Ile577Val variant.
GeneDx RCV000039411 SCV000233432 uncertain significance not specified 2016-06-14 criteria provided, single submitter clinical testing The I577V variant has been published as a variant of unknown significance in 59-year-old Caucasian female with a clinical diagnosis and family history of DCM, who also harbored a likely pathogenic variant in TTN gene (Pugh TJ et al., 2014). Furthermore, the variant has been identified by an outside laboratory in two Caucasian adults with DCM, both of whom carried another likely pathogenic variant (ClinVar SCV000063095.4; Landrum et al, 2016), and in other individuals referred for cardiomyopathy and arrhythmia testing at GeneDx. The I577V variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the I577V 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 that is conserved in mammals. However, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000542128 SCV000644995 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 577 of the DSC2 protein (p.Ile577Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs201845641, ExAC 0.06%), 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: 46170). 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.
Ambry Genetics RCV000621035 SCV000736644 uncertain significance Cardiovascular phenotype 2016-06-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624058 SCV000740322 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2017-02-07 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770535 SCV000901982 uncertain significance Cardiomyopathy 2017-02-08 criteria provided, single submitter clinical testing

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