Submissions for variant NM_001005242.3(PKP2):c.235C>T (p.Arg79Ter)

gnomAD frequency: 0.00005  dbSNP: rs121434420

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211843	SCV000061874	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-02-13	criteria provided, single submitter	clinical testing	The p.Arg79X variant in PKP2 has been previously identified in >15 individuals with ARVC and segregated with disease in >15 affected individuals from >5 families (Gerull 2004, Dalal 2006, van Tintelen 2006, den Haan 2009, Christensen 2010, van der Zwaag 2010, Larsen 2012, Noorman 2013, Rasmussen 2014, LMM data). This variant has also been identified in 1/111652 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 79, which is predicted to lead to a truncated or absent protein. In vitro functional studies support that this variant results in reduced PKP2 expression (Joshi-Mukherjee 2008). Heterozygous loss of PKP2 function is an established disease mechanism in individuals with ARVC. In summary, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2.
GeneDx	RCV000183722	SCV000236200	pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant reduces the expression level of plakophilin and alters desmosomal protein-protein interactions (Joshi-Mukherjee et al., 2008; Rasmussen et al., 2014); 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; This variant is associated with the following publications: (PMID: 31386562, 23810883, 24704780, 15489853, 16549640, 16567567, 20031617, 19955750, 21301620, 20829228, 22177269, 24125834, 25765472, 26800703, 21606396, 27532257, 20857253, 28152038, 23889974, 23178689, 30847666, 31737537, 31447099, 31402444, 20031616, 19084810, 33662488, 33232181, 32372669, 32522011, 31729605, 33500567)
Invitae	RCV000007146	SCV000288604	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg79*) 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 (rs121434420, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 19955750, 21301620, 21606396). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6754). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000246785	SCV000318240	pathogenic	Cardiovascular phenotype	2021-12-17	criteria provided, single submitter	clinical testing	The p.R79* pathogenic mutation (also known as c.235C>T), located in coding exon 2 of the PKP2 gene, results from a C to T substitution at nucleotide position 235. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been described in numerous individuals and families with arrhythmogenic right ventricular cardiomyopathy (ARVC) and was determined to be a Dutch founder mutation associated with reduced penetrance and variable expressivity (van der Zwaag PA et al. Neth Heart J. 2010;18(12):583-91). Functional in vitro analysis demonstrated poor localization to the cell membrane and altered desmosomal protein interactions with reduced expression (Joshi-Mukherjee R et al. Heart Rhythm. 2008;5:1715-1723). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000007146	SCV000731253	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2017-11-28	criteria provided, single submitter	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000007146	SCV000743461	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2014-10-08	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000007146	SCV000840033	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2018-01-30	criteria provided, single submitter	clinical testing	A heterozygous c.235C>T (p.R79*) pathogenic variant in the PKP2 gene was detected in this individual. This variant has been previously described in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (PMID 19955750, 15489853, 21301620, 21606396). In addition, experimental studies have shown that this variant results in reduced PKP2 protein expression, a loss of localization to sites of cell-cell contact and reduces interaction with connexin 43 protein in vitro (PMID 19084810). Therefore, we consider this variant to be pathogenic.
Eurofins Ntd Llc (ga)	RCV000183722	SCV000860205	pathogenic	not provided	2018-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001841230	SCV000918024	pathogenic	Cardiac arrhythmia	2018-02-28	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.235C>T (p.Arg79X) 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 (eg. c.397C>T, p.Gln133X; c.1211dupT, p.Val406fsX4; c.1237C>T, p.Arg413X). The variant allele was found at a frequency of 4.1e-06 in 246126 control chromosomes. c.235C>T has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, including multiple affected individuals from several families, and was reported to be a Dutch founder mutation (Van der Zwaag_PKP2_NethHeartJ_2010). At least one publication reports experimental evidence evaluating an impact on protein function. This report showed the mutant protein failed to preferentially localize to sites of cell-cell apposition, resulted in reduced abundance of Cx43 after R79x expression and prevented its physical interaction with both DP and Cx43 (Joshi-Mukherjee_2008). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. 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	RCV001190184	SCV001357621	pathogenic	Cardiomyopathy	2023-11-29	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 of the PKP2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Experimental studies have shown that the PKP2 protein expression was decreased by 50% in cells from a heterozygous carrier compared with wild type (PMID: 24704780). It has been shown that the mutant protein does not localize to sites of cell-cell contact and shows reduced ability to interact with connexin 43 protein (PMID: 19084810). This variant has been reported in multiple individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 19955750, 21301620, 21606396, 24704780, 25765472, 31386562), and is thought to be a founder mutation in the Dutch population (PMID: 21301620). This variant has been identified in 1/251328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on available evidence, this variant is classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000007146	SCV001468665	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2020-11-13	criteria provided, single submitter	research	ACMG codes:PVS1, PS4, PS3, PM2, PP1S
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000183722	SCV002009819	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000183722	SCV002497214	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	PKP2: PVS1, PM2, PS4:Supporting
Fulgent Genetics, Fulgent Genetics	RCV000007146	SCV002789328	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-10-25	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001190184	SCV004046187	pathogenic	Cardiomyopathy		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 2 of 14 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple individuals and families with arrhythmogenic right ventricular cardiomyopathy and was determined to be a Dutch founder mutation (PMID: 19955750, 15489853, 21301620, 30847666, 31386562, 21606396). Functional studies showed this variant leads to reduced PKP2 expression, poor localization to the cell membrane and altered desmosomal protein interactions (PMID: 19084810, 24704780). Loss-of-function variation in PKP2 is an established mechanism of disease (PMID: 19084810, 15489853). The c.235C>T (p.Arg79Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251328) and thus is presumed to be rare. Based on the available evidence, the c.235C>T (p.Arg79Ter) variant is classified as Pathogenic.
OMIM	RCV000007146	SCV000027342	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2004-11-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000183722	SCV000280413	pathogenic	not provided	2014-07-29	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.Arg79Stop (c.235 C>T) in the PKP2 gene. This variant has been reported in at least 20 unrelated individuals with ARVC. The variant was first reported by Gerull et al (2004) in six unrelated individuals with ARVC. Van Tintelen et al (2006) then reported the variant in five unrelated individuals with ARVC. The same group later published 12 unrelated ARVC cases with the variant (including some of their original cases) (van der Zwaag et al 2010). Haplotype analysis supported a founder effect. The authors provide segregation data for 8 families with 2-3 affected individuals with the variant in each family. There were no individuals with definite or probable ARVC who did not have the variant. Christensen et al (2010) reported another patient with ARVC and this variant. Klauke et al (2010) reported the variant in an additional case. Recently Kapplinger et al (2011) reported this variant in 8 cases of ARVC, though some may overlap with previously reported cases. This variant creates a stop codon 79 residues into the PKP2 protein; it is predicted to either prevent protein production via nonsense mediated mRNA decay or to create a truncated protein. Joshi-Mukherjee et al (2008) studied the variant in neonatal rat ventricular myocytes in culture. They found that a truncated protein was expressed, which failed to localize appropriately and reduced expression of connexin-43 and loss of expression of HSP90. Gerull B et al (2004) did not find the variant in 250 presumably healthy controls of unspecified ethnicity. Klauke et (2010) report that they did not find the variant in 363 control individuals of unspecified race. Christensen et al (2010) did not see the variant in 650 controls. Kapplinger et al did not observe the variant in 427 control individuals. Thus in total this variant has not been observed in at least 1690 control individuals.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000007146	SCV000733170	pathogenic	Arrhythmogenic right ventricular dysplasia 9		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000183722	SCV001919298	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000183722	SCV001955175	pathogenic	not provided		no assertion criteria provided	clinical testing