ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1660C>T (p.Gln554Ter) (rs878853170)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254959 SCV000321562 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing The Q554X variant in the DSC3 gene has previously been reported in association with ARVC (Xu et al., 2010; Gerull et al., 2013). Xu et al. (2010) identified a heterozygous Q554X variant in one individual diagnosed with ARVC. Gerull et al., (2013) identified homozygous Q554X variants in affected individuals from two large Hutterite families with a history of sudden death and severe biventricular cardiomyopathy, and concluded Q554X is a founder mutation in this population. In this study, heterozygous carriers of Q554X failed to meet task force criteria for a diagnosis of ARVC. This variant has also been observed in the homozygous state in other unrelated Hutterite individuals referred for ARVC genetic testing at GeneDx. Q554X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Functional studies revealed Q554X altered expression of the truncated DSC2 protein at the intercalated discs and confirmed the production of a stable, partially processed truncated protein product (Gerull et al., 2013). Other downstream nonsense variants in the DSC2 gene have been reported in HGMD in association with ARVC/D (Stenson et al., 2014). Furthermore, the Q554X pathogenic variant was not observed 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.In summary, Q554X in the DSC2 gene is interpreted as a pathogenic variant.
OMIM RCV000224990 SCV000281777 pathogenic ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11, WITH OR WITHOUT MILD PALMOPLANTAR KERATODERMA 2009-01-01 no assertion criteria provided literature only

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