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: 4
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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 2022-01-11 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 78974). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. 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 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, 23911551).
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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