Submissions for variant NM_001005242.3(PKP2):c.1780C>T (p.Gln594Ter)

gnomAD frequency: 0.00001  dbSNP: rs397517012

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211841	SCV000061856	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2010-06-22	criteria provided, single submitter	clinical testing	The Gln638X variant has been reported in one individual who presented with synco pe, right ventricular involvement, and ventricular tachycardia (Gerull et al, 20 05). In addition, the Gln638X variant leads to a premature stop at codon 638. T his alteration is predicted to lead to a truncated or absent protein. Loss of fu nction variants are an established mechanism of disease for the PKP2 gene, which makes it highly likely that the Gln638X variant is pathogenic.
GeneDx	RCV000183763	SCV000236244	pathogenic	not provided	2025-02-27	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23810883, 26743238, 30790397, 31737537, 30731207, 32268277, 32372669, 31402444, 31386562, 15489853, 35819174, 24967631, 35653365, 34120153)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531123	SCV000638874	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-12-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln638*) 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). This variant is present in population databases (rs397517012, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (PMID: 15489853, 23810883, 24967631, 26743238). ClinVar contains an entry for this variant (Variation ID: 45049). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000211841	SCV000740392	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2016-05-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175485	SCV001339078	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2020-03-30	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1912C>T (p.Gln638X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 252142 control chromosomes. c.1912C>T has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Gerull_2004, Wlodarska_2008, Perrin_2013, Alcalde_2014, Adler_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001188338	SCV001355375	pathogenic	Cardiomyopathy	2023-08-10	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. This variant has been reported in over 30 individuals from multiple families affected with arrythmogenic right ventricular cardiomyopathy (PMID: 15489853, 23810883, 24967631, 26743238). This variant has been identified in 2/282710 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000183763	SCV001501411	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000531123	SCV002810506	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-09-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001188338	SCV004239574	pathogenic	Cardiomyopathy	2022-07-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000211841	SCV004845970	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2024-02-08	criteria provided, single submitter	clinical testing	The c.1912C>T (p.Gln638*) variant in PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been reported in multiple individuals (>15) affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC/D) (PMID:23810883, 15489853, 24967631). Loss of function variants are known to be pathogenic for PKP2 (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Loss of function variants downstream of this variant are reported to be pathogenic in multiple individuals with ARVC (PMID:15489853, 28431057, 30790397) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 201998). This variant was found to be rare (2/282710; 0.0007%) in the general population database gnomAD and classified as pathogenic by multiple ClinVar submitters (ClinVar ID: 45049). Therefore, the c.1912C>T (p.Gln638*) variant in PKP2 gene is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000531123	SCV005045692	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2020-04-14	criteria provided, single submitter	clinical testing	The c.1912C>T (p.Gln638*) variant in PKP2 gene, that encodes for plakophilin 2, creates a premature termination codon that is predicted to lead to an absent or truncated protein product. This variant has been reported in multiple individuals (>15) affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC/D) (PMID:23810883, 15489853, 24967631). Loss of function variants are known to be pathogenic for PKP2 (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Loss of function variants downstream of this variant are reported to be pathogenic in multiple individuals with ARVC (PMID:15489853, 28431057, 30790397) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 201998). This variant was found to be rare (2/282710; 0.0007%) in the general population database gnomAD and classified as pathogenic by multiple ClinVar submitters (ClinVar ID: 45049). Therefore, the c.1912C>T (p.Gln638*) variant in PKP2 gene is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000183763	SCV005414067	pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing	PM2, PS4, PVS1
Institute of Human Genetics, Heidelberg University	RCV000531123	SCV005871391	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-09-23	criteria provided, single submitter	clinical testing