Submissions for variant NM_001005242.3(PKP2):c.1717C>T (p.Gln573Ter)

dbSNP: rs201405287

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV003532039	SCV004358872	pathogenic	Cardiomyopathy	2023-03-08	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study with epicardial cells derived from induced human pluripotent stem cells from a carrier individual has shown that this variant results in the loss of expression of PKP2 in both mRNA and protein levels when compared to the isogenic control cell line generated by targeted gene correction (PMID: 34550725). This variant has been reported in at least two unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 24920660, 25820315, 26850880, 28588093, 32294163). 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.
All of Us Research Program, National Institutes of Health	RCV003996838	SCV004830234	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study with epicardial cells derived from induced human pluripotent stem cells from a carrier individual has shown that this variant results in the loss of expression of PKP2 in both mRNA and protein levels when compared to the isogenic control cell line generated by targeted gene correction (PMID: 34550725). This variant has been reported in at least two unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 24920660, 25820315, 26850880, 28588093, 32294163). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000183759	SCV000280409	likely pathogenic	not provided	2011-08-01	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gln617Stop (c.1849 C>T) in PKP2 This variant is novel. Since it creates a new stop codon it is predicted to lead to a truncated protein product or no protein product at all, due to nonsense mediated mRNA decay. The majority of pathogenic PKP2 variants are ones that lead to truncated or aberrant protein product (Van Tintelen et al 2006, den Haan et al 2009). Many nonsense variants in PKP2 have been reported in ARVC cases, including one at the neighboring codon (p.Tyr616Stop), which has been reported multiple times in association with ARVC (van Tintelen et al 2006, Bhuiyan et al 2009, Kapplinger et al 2011). Two recent reports at the Heart Rhythm Society meeting noted more severe phenotypes in individuals with PKP2 nonsense (or other null or truncating) variants compared to those with PKP2 missense variants. A recent analysis of rare variants in desmosomal genes in healthy individuals found several PKP2 missense variants but no nonsense variants (Kapplinger et al 2011). These data further support the pathogenic role of nonsense variants in PKP2. This variant has not been reported in dbSNP (as of June 2011). This variant was not seen in the 427 presumably healthy individuals studied by Kapplinger et al (2011).