ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1689-2A>G (rs1555143143)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520771 SCV000618103 pathogenic not provided 2016-05-16 criteria provided, single submitter clinical testing Although the c.1689-2 A>G variant has not been reported as a pathogenic variant or as a benign variant to our knowledge, it 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. Other splice site variants in the PKP2 gene, including one that impacts the same splice acceptor site (c.1689-1 G>C) have been reported in association with ARVC (Fressart et al., 2010; Stenson et al., 2014). Furthermore, the c.1689-2 A>G variant 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.1689-2 A>G in the PKP2 gene is interpreted as a pathogenic variant.
Invitae RCV000530347 SCV000638871 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-05-18 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 has not been reported in the literature in individuals with a PKP2-related disease. In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.

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