ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2300-1G>A (rs1060501184)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456706 SCV000545239 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-10-29 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the PKP2 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PKP2-related disease. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating 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.
GeneDx RCV000599273 SCV000710043 likely pathogenic not provided 2018-01-31 criteria provided, single submitter clinical testing The c.2300-1G>A variant in the PKP2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 11. It is predicted to cause abnormal gene splicing, either leading to 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. The c.2300-1G>A variant is not observed in large population cohorts (Lek et al., 2016). Therefore, based on the ACMG recommendations, c.2300-1G>A is interpreted as an expected pathogenic sequence change.

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