ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1379-1998C>T

gnomAD frequency: 0.00001  dbSNP: rs151212477
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000262179 SCV000332702 pathogenic not provided 2015-07-10 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000262179 SCV002502890 likely pathogenic not provided 2022-02-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002514319 SCV003025843 pathogenic Arrhythmogenic right ventricular dysplasia 9 2024-12-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg497*) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 17041889, 23911551). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 78974). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health RCV004806048 SCV005429469 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2023-12-10 criteria provided, single submitter clinical testing The c.1489C>T (p.Arg497*) variant in exon 6 of PKP2 gene, encoding plakophilin 2, creates a premature termination codon that is predicted to lead to absent or truncated protein product. This variant has been reported in an individual whose postmortem biopsy showed dilated cardiomyopathy (DCM), but the association of PKP2 variants with DCM is controversial, leaving it unclear if this variant caused this family?s DCM and sudden cardiac death (PMID: 35470680). This variant has also been reported in an individual with arrhythmogenic cardiomyopathy (PMID: 33652588). Loss of function variants are known to be pathogenic for PKP2 (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). This variant is found to be rare (2/217850; 0.000009181) in the general population database (gnomAD). This variant is reported in the ClinVar database (ClinVar ID: 78974). Therefore, the c.1489C>T (p.Arg497*) variant in the PKP2 gene is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences RCV003398654 SCV004104133 uncertain significance PKP2-related disorder 2024-04-25 no assertion criteria provided clinical testing The PKP2 c.1489C>T variant is predicted to result in premature protein termination (p.Arg497*). This variant was reported in an individual with arrhythmogenic cardiomyopathy (Vallverdú-Prats et al. 2021. PubMed ID: 33652588). This variant was also reported in an individual with dilated cardiomyopathy without evidence of arrhythmogenic right ventricular dysplasia (Smith et al. 2022. PubMed ID: 35470680). While loss of function is an established mechanism for PKP2-associated arrhythmogenic right ventricular dysplasia, this variant is located in an alternative exon of a transcript (NM_004572) which is minimally expressed in human heart tissues (Gandjbakhch et al. 2011. PubMed ID: 21378009). This variant is referred to as c.1379-1998C>T (intronic) with the transcript (NM_001005242) which is predominantly expressed in human heart tissues. A canonical splice site variant flanking this alternate exon, NM_004572 c.1379-1G>A (NM_001005242 c.1379-2109G>A), has been documented in ~120 heterozygous individuals in gnomAD v4.1.0 (https://gnomad.broadinstitute.org/), supporting that this alternate exon may not be critical for human heart development. The c.1489C>T (p.Arg497*) variant is reported in 0.0020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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