ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1171-2A>G (rs794729133)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183805 SCV000236286 pathogenic not provided 2016-08-22 criteria provided, single submitter clinical testing The c.1171-2 A>G splice site variant in the PKP2 gene has been previously reported in multiple individuals in association with ARVC (Dalal et al., 2006; Xu et al., 2010; Bao et al., 2013; Ermakov et al., 2014). The c.1171-2 A>G variant destroys the canonical splice acceptor site in intron 4 and is predicted to cause abnormal gene splicing. This variant 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 variants in the PKP2 gene have been reported in HGMD in association with ARVC (Stenson et al., 2014). Furthermore, c.1171-2 A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.1171-2 A>G in the PKP2 gene is interpreted as a pathogenic variant.
Invitae RCV001048332 SCV001212331 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-01-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 of the PKP2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16549640, 25196244). ClinVar contains an entry for this variant (Variation ID: 202030). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170219 SCV001332776 pathogenic Cardiomyopathy 2018-04-04 criteria provided, single submitter clinical testing

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