ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1627del (p.Val543fs)

dbSNP: rs397517008
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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, Mass General Brigham Personalized Medicine RCV000038185 SCV000061852 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2010-12-14 criteria provided, single submitter clinical testing The Val587fs variant has not been reported in the literature and has not been pr eviously detected by our laboratory. This variant is predicted to cause a frame shift, which alters the protein's amino acid sequence beginning at codon 587 and leads to a premature stop codon 69 amino acids downstream. This alteration is t hen predicted to lead to a truncated or absent protein (loss of function). Patho genic loss of function variants are common in the PKP2 gene, which makes it high ly likely that the Val587fs is pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001525490 SCV001735623 pathogenic Cardiomyopathy 2020-05-24 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 8 of the PKP2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx RCV002255263 SCV002526465 pathogenic not provided 2023-09-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31402444, 20857253, 31386562, 34120153)
Ambry Genetics RCV002408518 SCV002716618 pathogenic Cardiovascular phenotype 2018-04-12 criteria provided, single submitter clinical testing The c.1759delG pathogenic mutation, located in coding exon 8 of the PKP2 gene, results from a deletion of one nucleotide at nucleotide position 1759, causing a translational frameshift with a predicted alternate stop codon (p.V587Sfs*69). This alteration has been reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort (Tan BY et al. J Cardiovasc Transl Res, 2010 Dec;3:663-73). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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