ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1034+1G>T

dbSNP: rs869025496
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000218069 SCV000271256 likely pathogenic Cardiomyopathy 2016-03-10 criteria provided, single submitter clinical testing The c.1034+1G>T variant in PKP2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant occurs in the i nvariant region (+/- 1,2) of the splice consensus sequence and is predicted to c ause altered splicing leading to an abnormal or absent protein. Splicing variant s and other truncating variants in PKP2 are well-reported in individuals with AR VC (ARVD/C Genetic Variant Database, http://arvcdatabase.info; Human Gene Mutati on Database). In summary, although additional studies are required to fully esta blish its clinical significance, the c.1034+1G>T variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000692391 SCV000820212 likely pathogenic Arrhythmogenic right ventricular dysplasia 9 2019-05-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 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 not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 228286). 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). 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.

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