ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1170+1G>C

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003508858 SCV004295871 pathogenic Arrhythmogenic right ventricular dysplasia 9 2023-07-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the PKP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443; Invitae). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV004369275 SCV005022704 pathogenic Cardiovascular phenotype 2021-12-01 criteria provided, single submitter clinical testing The c.1170+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 4 of the PKP2 gene. This alteration was detected in a genetic testing cohort in one individual reported to have arrhythmogenic right ventricular cardiomyopathy (ARVC), but clinical details were not provided (Walsh R et al. Genet Med, 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Another alteration impacting the same donor site (c.1170+1G>A) has been described in a patient with a clinical diagnosis of ARVC (Hermida A et al. Eur J Heart Fail, 2019 06;21:792-800). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

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