ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1643del (p.Gly548fs) (rs794729137)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183812 SCV000236294 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing The c.1643delG pathogenic variant in the PKP2 gene has been reported previously in association with ARVC (Gerull et al., 2004; Perrin et al., 2013). The c.1643delG variant was previously reported as c.1642delG (p.Val548fsX562) (Gerull et al., 2004) and c.1643delG (p.Val548fsX562) (Perrin et al., 2013), due to differences in mutation nomenclature. This variant causes a shift in reading frame starting at codon glycine 548, changing it to a valine, and creating a premature stop codon at position 15 of the new reading frame, denoted p.Gly548ValfsX15. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the PKP2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1643delG variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000217215 SCV000271258 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2018-07-05 criteria provided, single submitter clinical testing The p.Gly548ValfsX15 variant in PKP2 has been reported in at least 7 individuals with either possible or definitive diagnosis of ARVC and segregated with diseas e in 1 affected relative (Gerull 2004, Dalal 2006, Perrin 2013, Fressart 2010, D alal 2006, LMM data). This variant is absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino ac id sequence beginning at position 548 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. Heterozygous loss of function of the PKP2 gene is an est ablished disease mechanism in ARVC. In summary, this variant is pathogenic in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2.
Invitae RCV000229546 SCV000288597 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-07-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly548Valfs*15) 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 reported in the literature in individuals affected with arrythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 20031617, 20400443, 24070718, 24704780, 24967631). This variant is also known as c.1642delG in the literature. ClinVar contains an entry for this variant (Variation ID: 202035). 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 RCV000619593 SCV000734877 pathogenic Cardiovascular phenotype 2018-08-02 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000229546 SCV000803791 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-10-06 criteria provided, single submitter clinical testing

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