ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2299+1G>A (rs794729116)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183774 SCV000236255 pathogenic not provided 2012-05-01 criteria provided, single submitter clinical testing c.2299+1 G>A: IVS11+1 G>A in intron 11 of the PKP2 gene (NM_004572.3). The c.2299+1 G>A mutation in the PKP2 gene has also not been reported previously as a disease-causing mutation, however this mutation destroys the consensus splice donor site of intron 11 and is expected to cause abnormal gene splicing. Three splice prediction algorithms concur that c.2299+1 G>A results in the loss of the normal splice donor site. This mutation is predicted to lead to either an abnormal message, which is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In addition, other splice site mutations (c.2489+1 G>A, c.2489+4 C>A) in the PKP2 gene have been reported in association with ARVC (Van der Zwaag P et al., 2009). Therefore, c.2299+1 G>A in the PKP2 gene is interpreted to be a disease-causing mutation. The variant is found in ARVC panel(s).
Ambry Genetics RCV000622076 SCV000737878 likely pathogenic Cardiovascular phenotype 2017-01-09 criteria provided, single submitter clinical testing The c.2299+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 11 of the PKP2 gene. This alteration has been described in two individuals from the same family reported to have arrhythmogenic right ventricular cardiomyopathy (ARVC) (Adler A et al. Circ Arrhythm Electrophysiol. 2016;9:e003440). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000183774 SCV000748029 pathogenic not provided 2016-12-22 criteria provided, single submitter clinical testing

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