ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2357+1G>T

dbSNP: rs111517471
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183715 SCV000236193 pathogenic not provided 2018-04-05 criteria provided, single submitter clinical testing c.2489+1 G>T: IVS12+1 G>T in intron 12 of the PKP2 gene (NM_004572.3). The c.2489+1 G>T mutation in the PKP2 gene has been published previously in association with ARVC (DenHaan et al., 2009). The mutation destroys the canonical splice donor site in intron 12 and is expected to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the PKP2 gene have been reported in association with ARVC. In summary, c.2489+1 G>T in the PKP2 gene is interpreted as a disease-causing mutation. The variant is found in ARVC panel(s).
Institute of Human Genetics, University of Leipzig Medical Center RCV001262835 SCV001440850 likely pathogenic Arrhythmogenic right ventricular dysplasia 9 2019-01-01 criteria provided, single submitter clinical testing
Invitae RCV001262835 SCV004295863 pathogenic Arrhythmogenic right ventricular dysplasia 9 2023-12-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 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 arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 20031616, 20031617, 21822014, 22214898). ClinVar contains an entry for this variant (Variation ID: 45071). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000038212 SCV000061880 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2009-10-07 no assertion criteria provided clinical testing

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