ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1780C>T (p.Gln594Ter) (rs397517012)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211841 SCV000061856 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2010-06-22 criteria provided, single submitter clinical testing The Gln638X variant has been reported in one individual who presented with synco pe, right ventricular involvement, and ventricular tachycardia (Gerull et al, 20 05). In addition, the Gln638X variant leads to a premature stop at codon 638. T his alteration is predicted to lead to a truncated or absent protein. Loss of fu nction variants are an established mechanism of disease for the PKP2 gene, which makes it highly likely that the Gln638X variant is pathogenic.
GeneDx RCV000183763 SCV000236244 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing The Q638X pathogenic variant in the PKP2 gene has been previously reported in multiple individuals in association with ARVC and has been shown to segregate with ARVC in at least one relative from one family (Gerull et al., 2004; Perrin et al., 2013; Alcade et al., 2014; Adler et al., 2016). It has also been observed in other individuals referred for ARVC genetic testing at GeneDx. Q638X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the PKP2 gene have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Furthermore, the Q638X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Invitae RCV000531123 SCV000638874 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 638 (p.Gln638*) of the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853). This particular variant has been reported in the literature in multiple families and other unrelated individuals affected with arrythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (PMID: 15489853, 23810883, 24967631, 26743238). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000211841 SCV000740392 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2016-05-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175485 SCV001339078 pathogenic Arrhythmogenic right ventricular dysplasia/cardiomyopathy 2020-03-30 criteria provided, single submitter clinical testing Variant summary: PKP2 c.1912C>T (p.Gln638X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 252142 control chromosomes. c.1912C>T has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Gerull_2004, Wlodarska_2008, Perrin_2013, Alcalde_2014, Adler_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV001188338 SCV001355375 pathogenic Cardiomyopathy 2019-10-01 criteria provided, single submitter clinical testing

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