The relationship between PKP2 and arrhythmogenic right ventricular cardiomyopathy (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of September, 2018. Variants in PKP2 were first reported in humans with this disease as early as 2004 (Gerull et al., PMID: 15489853). PKP2 is the major causative gene for ARVC and accounts for 34%-74% of cases (McNAlly et al., 2005; PMID: 20301310). There are over 250 PKP2 variants listed in ClinVar for ARVC (missense, nonsense, frameshift, complex rearrangements, etc) (Novelli et al., 2018; PMID: 30619891). This gene-disease relationship is well-known and therefore a significant amount of case-level data, segregation data and experimental data is available in the literature, therefore the maximum score for both genetic evidence and experimental evidence has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. This gene-disease relationship is supported by animal models, in vitro assays, and protein interactions. In summary, PKP2 is definitively associated with autosomal dominant ARVC. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Arrythmogenic Right Ventricular Cardiomyopathy Gene Curation Expert Panel on October, 26, 2018 (SOP Version 6).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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