ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1511-2A>T (rs1453983744)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619338 SCV000734940 pathogenic Cardiovascular phenotype 2017-12-04 criteria provided, single submitter clinical testing Well-characterized mutation at same position;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);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001115 SCV001158253 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-03-13 criteria provided, single submitter clinical testing The PKP2 c.1511-2A>T variant (rs1453983744), to our knowledge, is not reported in the medical literature, but another variant at this nucleotide has been identified in an individual with arrhythmogenic right ventricular dysplasia/cardiomyopathy and was shown to alter splicing (Groeneweg 2014). The identified variant is reported in ClinVar (Variation ID: 518485) and is found in the general population with an allele frequency of 0.0004% (1/249,604 alleles) in the Genome Aggregation Database. This variant abolishes the canonical splice acceptor site of intron 6, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic.
Invitae RCV001001115 SCV001224673 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 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). Disruption of this splice site has been observed in an individual affected with arrythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 25087486). ClinVar contains an entry for this variant (Variation ID: 518485). 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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