ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1481G>A (p.Trp494Ter) (rs193922672)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000030359 SCV000061841 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2019-04-12 criteria provided, single submitter clinical testing The p.Trp538X variant in PKP2 has been reported in >15 individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and segregated with disease in 3 affected relatives from 2 families (Dalal 2006, Den Haan 2009, Barahona Dussault 2009, Xu 2010, Tan 2010, Quarta 2011, Baskin 2013, Philips 2014, Adler 2016, LMM data). It was also identified in 1 child that died unexpectedly who also carried a pathogenic variant in CACNA1C (Dewar 2017) and has also been reported by other clinical laboratories in ClinVar (Variation ID 36680). Additionally, this variant was identified in 2 asymptomatic individuals (Perrin 2013) and in 0.03% (3/10078) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 538, which is predicted to lead to a truncated or absent protein. Loss of function of the PKP2 gene is strongly associated to autosomal dominant ARVC. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PVS1, PS4, PM2, PP1.
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).
Blueprint Genetics RCV000030359 SCV000264144 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-08-31 criteria provided, single submitter clinical testing
Invitae RCV000470376 SCV000545252 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-10-17 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.
Ambry Genetics RCV000621931 SCV000737692 pathogenic Cardiovascular phenotype 2019-04-25 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
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.
Fulgent Genetics,Fulgent Genetics RCV000470376 SCV000893979 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-10-31 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000470376 SCV000993576 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-09-21 criteria provided, single submitter research
Color RCV001189477 SCV001356774 pathogenic Cardiomyopathy 2019-02-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000030359 SCV000053026 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-04-03 no assertion criteria provided clinical testing

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