ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.337-2A>T (rs786204389)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183723 SCV000236201 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing The c.337-2 A>T variant in the PKP2 has been reported previously in association with ARVC (Bhonsale A et al., 2013). This variant destroys the canonical splice acceptor site in intron 2 and is predicted to cause abnormal gene splicing. The 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 variant in the PKP2 gene have been reported in association with ARVC.
Ambry Genetics RCV000254457 SCV000320683 pathogenic Cardiovascular phenotype 2015-12-20 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000543165 SCV000638898 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-31 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 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 particular variant has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 23671136, 27532257, Invitae Database). ClinVar contains an entry for this variant (Variation ID: 188654). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168929 SCV000711730 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2019-01-31 criteria provided, single submitter clinical testing The c.337-2A>T variant in PKP2 has been reported in 3 individual with ARVD/C (Bhonsale 2013, Walsh 2017) and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 188654). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the PKP2 gene is an established disease mechanism in individuals with arrhythmogenic right ventricular cardiomyopathy. In summary, although additional studies are required to fully establish its clinical significance, the c.337-2A>T variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS4_Supporting

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