ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1689-1G>C (rs78897684)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183751 SCV000236232 pathogenic not provided 2018-09-05 criteria provided, single submitter clinical testing The c.1689-1 G>C variant in the PKP2 gene has been previously reported in multiple individuals with ARVC (Fressart et al., 2010; Zaidi et al., 2015; Walsh et al., 2017). In one of these probands with ARVC, c.1689-1 G>C was found in conjunction with a missense variant in the DSP gene, and both variants co-segregated with ARVC in an affected relative (Zaidi et al., 2015). This variant has also been reported in other individuals referred for ARVC genetic testing at GeneDx. The c.1689-1 G>C variant destroys the canonical splice acceptor site in intron 7 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. Numerous other splice site variants in the PKP2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Additionally, another variant at the adjacent nucleotide within the same splice acceptor site (c.1689-2A>G) has been reported at GeneDx in association with ARVC, supporting the functional importance of this splice acceptor site region. Furthermore, the c.1689-1 G>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000183751 SCV000748002 pathogenic not provided 2017-07-26 criteria provided, single submitter clinical testing
Invitae RCV000702665 SCV000831528 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-07-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the PKP2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs78897684, ExAC 0.01%). This variant has been reported in several individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 19863551, 20400443, 27532257). This variant is also known as 1690-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 201989). 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.

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