ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1132C>T (p.Gln378Ter) (rs397516986)

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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 RCV000211737 SCV000061815 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2018-10-24 criteria provided, single submitter clinical testing The p.Gln378X variant in PKP2 has been identified in >15 individuals with ARVC ( Watkins 2009, Fressart 2010, Bhonsale 2013, Kumar 2013 Ohno 2013, Kumar 2013, Ph ilips 2014, Groeneweg 2015, Torkamani 2016, Sonoda 2017, Wada 2017, Orgeron 2017 , LMM data) and was reported to be de novo in 1 case (Horie 2008). It has also b een reported by other clinical laboratories in ClinVar (Variation ID # 45010) an d has been identified in 2/129154 European chromosomes by gnomAD (http://gnomad. This nonsense variant leads to a premature termination codo n at position 378, which is predicted to lead to a truncated or absent protein. Loss of function of the PKP2 gene is an established disease mechanism in in indi viduals autosomal dominant ARVC. In summary, this variant meets criteria to be c lassified as pathogenic for autosomal dominant ARVC. ACMG/AMP criteria applied: PVS1, PS4, PM2, PM6.
GeneDx RCV000183735 SCV000236215 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing The Q378X pathogenic variant in the PKP2 gene has been reported in multiple unrelated individuals from different ethnic backgrounds in association with ARVC (Watkins et al., 2009; Fressart et al., 2010; Bhonsale et al., 2013; Ohno et al., 2013; Philips et al., 2014; Groeneweg et al., 2015; Torkamani et al., 2016; Walsh et al., 2017; Sonoda et al., 2017; Wada et al., 2017). The Q378X variant 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 Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Furthermore, the Q378X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Ambry Genetics RCV000621345 SCV000734875 pathogenic Cardiovascular phenotype 2016-01-12 criteria provided, single submitter clinical testing
Invitae RCV000798628 SCV000938253 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-11-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln378*) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 19880068, 27532257, 23514727). ClinVar contains an entry for this variant (Variation ID: 45010). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics,Johns Hopkins University RCV000798628 SCV000996041 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-07-26 criteria provided, single submitter clinical testing
Color RCV001179300 SCV001343931 pathogenic Cardiomyopathy 2019-11-15 criteria provided, single submitter clinical testing

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