ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1556+1G>A (rs397517003)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038177 SCV000061844 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2019-03-06 criteria provided, single submitter clinical testing The c.1688+1G>A variant in PKP2 has been identified in 2 individuals with ARVC (Fressart 2010, LMM data) and 1/113356 European chromosomes by gnomAD ( This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the PKP2 gene is an established disease mechanism in autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC). This variant has also been reported in ClinVar (Variation ID 45038). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
GeneDx RCV000183750 SCV000236231 pathogenic not provided 2017-12-07 criteria provided, single submitter clinical testing The c.1688+1 G>A mutation in the PKP2 gene has been reported previously in one individual who met task force criteria for ARVC, and it was absent from 600 Caucasian control alleles in this study (Fressart V et al., 2010). The mutation destroys the canonical splice donor site in intron 7 and is expected to cause abnormal gene splicing. This may lead to loss of protein function due to protein truncation or absence of protein from this allele due to mRNA decay. Furthermore, population studies performed at GeneDx demonstrate that c.1688+1 G>A was not present in up to 400 control alleles of individuals of Caucasian and African American backgrounds, indicating that it is not a common benign variant in these populations. The variant is found in ARVC panel(s).
Invitae RCV000689131 SCV000816771 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-05-11 criteria provided, single submitter clinical testing This sequence change affects a donor 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 not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 20400443). This variant is also described as IVS7+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 45038). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color RCV001181319 SCV001346440 likely pathogenic Cardiomyopathy 2019-10-14 criteria provided, single submitter clinical testing

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