ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1613G>A (p.Trp538Ter) (rs193922672)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621931 SCV000737692 pathogenic Cardiovascular phenotype 2016-08-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Blueprint Genetics, RCV000030359 SCV000264144 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-08-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000470376 SCV000893979 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000183748 SCV000236229 pathogenic not provided 2018-09-11 criteria provided, single submitter clinical testing The W538X pathogenic variant in the PKP2 gene has been reported multiple times in association with ARVC (Dalal et al., 2006; den Haan et al., 2009; Barahona-Dussault et al., 2010; Tan et al., 2010; Xu et al., 2010; Quarta et al., 2011, Baskin et al., 2013, Philips et al., 2014; Shestak et al., 2014). In these reports, the W538X variant was identified in multiple individuals who met task force criteria for ARVC, some of whom had an age of onset at 30 years or younger (Dalal et al., 2006; Barahona-Dussault et al., 2010; Tan et al., 2010; Xu et al., 2010; Quarta et al., 2011; Baskin et al., 2013; Philips et al., 2014). This variant has also been observed in other unrelated individuals referred for ARVC genetic testing at GeneDx. This variant is predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. Other downstream nonsense variants in the PKP2 gene have been reported in HGMD in association with ARVC (Stenson et al., 2014). Additionally, W538X is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Gharavi Laboratory,Columbia University RCV000183748 SCV000809449 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000470376 SCV000840042 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-11-10 criteria provided, single submitter clinical testing The c.1613G>A (p.Trp538*) nonsense variant in the PKP2 gene is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) [PMID 16549640, 19863551, 20031617, 20152563, 20857253, 21606390, 26743238]. This variant in the PKP2 gene is classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000030359 SCV000053026 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-04-03 no assertion criteria provided clinical testing
Invitae RCV000470376 SCV000545252 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-10-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp538*) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs193922672, ExAC 0.003%). This variant has been reported in the literature in individuals affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 16549640, 20031617, 20152563, 19863551, 26743238). ClinVar contains an entry for this variant (Variation ID: 36680). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000030359 SCV000061841 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2014-04-02 criteria provided, single submitter clinical testing The Trp538X variant in PKP2 leads to a premature termination codon at position 5 38, which is predicted to lead to a truncated or absent protein. This variant wa s absent from large population studies but has been reported in at least 9 indiv iduals with ARVC, two of whom carried other ARVC variants and presented with ear ly onset disease (Den Haan 2009, Barahona Dussault 2009, Xu 2010, Quarta 2011, B askin 2013). It was also identified in 1 asymptomatic teenager and 1 elderly in dividual with PVCs (Perrin 2013). Our laboratory has detected this nonsense vari ant in 3 individuals with ARVC and 2 affected relatives. In summary, this varian t is likely to be pathogenic, though additional studies are required to fully es tablish its clinical significance.

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