Submissions for variant NM_001005242.3(PKP2):c.1237C>T (p.Arg413Ter)

gnomAD frequency: 0.00005  dbSNP: rs372827156

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038155	SCV000061821	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2016-03-21	criteria provided, single submitter	clinical testing	The p.Arg413X variant in PKP2 has been identified in >10 individuals with ARVC a nd segregated with disease in at least 4 affected relatives from three families (Syrris 2006, Unsold 2006, Unsoeld 2009, den Haan 2009, Fressart 2010, Tan 2010, Quarta 2011, Baskin 2013, Philips 2014, Campuzano 2014, LMM data). This varian t has also been reported by other clinical laboratories in ClinVar (Variation ID : 45016) and has been identified in 4/282766 pan ethnic chromosomes by gnomAD (h ttp://gnomad.broadinstitute.org). Please note that for diseases with clinical va riability and reduced penetrance, pathogenic variants may be present at a low fr equency in the general population. Over-expression of this variant in mice incre ased right ventricular size and shortened ventricular action potential durations (Unsoeld 2009). This nonsense variant leads to a premature termination codon at position 413, which is predicted to lead to a truncated or absent protein. Het erozygous loss of function of the PKP2 gene is an established disease mechanism in ARVC. In summary, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner based upon the predicted impact to the protein, presence in multiple affected individuals, segregation studies, low fr equency in the general population and functional studies. ACMG/AMP Criteria appl ied: PVS1, PS3_Moderate, PM2, PP1_Supportive, PS4_Moderate.
GeneDx	RCV000183740	SCV000236220	pathogenic	not provided	2022-02-03	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients with ARVC referred for genetic testing at GeneDx and in published literature (Syrris et al., 2006; den Haan et al., 2009; Unsoeld et al., 2009; Fressart et al., 2010; Tan et al., 2010; Quarta et al., 2011; Philips et al., 2014; Alcalde et al., 2014; Walsh et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 21606390, 27831900, 23299917, 25447171, 25637381, 25525159, 24967631, 20031617, 20857253, 20400443, 24585727, 16415378, 27532257, 28471438, 23812740, 32659924, 32372669, 31386562, 31402444, 31156706, 33684294, 26314686, 29997227, 30790397, 28588093, 29606362, 33087929, 32686758, 33232181, 26582918, 27535533)
Invitae	RCV000471559	SCV000545238	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg413*) 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 (rs372827156, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 20857253, 21606390, 24967631). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 45016). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588929	SCV000698461	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2021-11-07	criteria provided, single submitter	clinical testing	Variant summary: PKP2 c.1237C>T (p.Arg413X) 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 1.2e-05 in 252358 control chromosomes. c.1237C>T has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example, Syrris_2006, Fressart_2010, den Haan_2009, Tan_2010, Unsoeld_2006, Unsoeld_2009). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in an animal model. The most pronounced variant effect results in a recapitulation of the right ventricular phenotype in a transgenic mouse overexpressing this variant (Unsoeld_2009). Nine 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.
Ambry Genetics	RCV000619035	SCV000734891	pathogenic	Cardiovascular phenotype	2020-12-28	criteria provided, single submitter	clinical testing	The p.R413* pathogenic mutation (also known as c.1237C>T), located in coding exon 5 of the PKP2 gene, results from a C to T substitution at nucleotide position 1237. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been described in multiple unrelated individuals with confirmed or suspected arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), and has also been reported to segregate with disease in several families (Syrris P et al. Circulation. 2006;113(3):356-64; den Haan AD et al. Circ Cardiovasc Genet. 2009;2(5):428-35; Unsoeld B et al. Circulation. 2009;120:S618; Fressart V et al. Europace. 2010;12(6):861-8; Quarta G et al. Circulation. 2011;123(23):2701-9; Campuzano O et al. Forensic Sci Int. 2014;245C:30-37; te Riele AS et al. JACC:Clin Electrophysiol. 2015;1(6):551-60; Campuzano O et al. Front Genet. 2019 May;10:450). 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.
Illumina Laboratory Services, Illumina	RCV000471559	SCV000915591	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2018-08-29	criteria provided, single submitter	clinical testing	The PKP2 c.1237C>T (p.Arg413Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of available literature, the p.Arg413Ter variant has been reported in a heterozygous state in over ten individuals with arrhythmogenic right ventricular cardiomyopathy and in one individual from a cohort of probands who died from sudden cardiac death (Syrris et al. 2006; den Haan et al. 2009; Fressart et al. 2010; Quarta et al. 2011; Alcade et al. 2014; Philips et al. 2014; Campuzano et al. 2014). The p.Arg413Ter variant was absent from 1500 control subjects and is reported at a frequency of 0.000014 in the African population of the Genome Aggregation Database. Based on the clinical evidence and the potential impact of stop-gained variants, the p.Arg413Ter variant is classified as pathogenic for arrhythmogenic right ventricular cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000471559	SCV001192819	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2020-01-14	criteria provided, single submitter	research
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170218	SCV001332775	pathogenic	Cardiomyopathy	2019-06-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170218	SCV001342800	pathogenic	Cardiomyopathy	2023-05-09	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 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 ten individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 20857253, 21606390, 31319917, 32659924, 34191271). This variant has been shown to segregate with disease in eleven individuals from two families with arrhythmogenic cardiomyopathy (PMID:24967631, 31156706) and has also been observed in an unaffected adult family member who showed cardiac abnormalities (PMID: 31156706). This variant has also been reported in an asymptomatic individual with a family history of sudden cardiac death (PMID: 29997227). This variant has been identified in 4/282766 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 the available evidence, this variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000183740	SCV001501413	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000471559	SCV002810385	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2021-12-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952434	SCV004773712	pathogenic	PKP2-related condition	2023-12-21	criteria provided, single submitter	clinical testing	The PKP2 c.1237C>T variant is predicted to result in premature protein termination (p.Arg413*). This variant has been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (Syrris et al. 2006. PubMed ID: 16415378; Philips et al. 2014. PubMed ID: 24585727; Table S1A - Walsh et al. 2017. PubMed ID: 27532257) and an individual with sudden unexplained death (Campuzano et al. 2014. PubMed ID: 25447171). This variant has also been reported in multiple unaffected individuals (Natarajan et al. 2016. PubMed ID: 27831900; Haggerty et al. 2018. PubMed ID: 29997227). In ClinVar, this variant has been in interpreted as pathogenic by multiple labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/45016/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Loss-of-function variants in PKP2 are a known cause of disease and are expected to be pathogenic (Gerull et al. 2004. PubMed ID: 15489853). Based on the available evidence, this variant is interpreted as pathogenic.
CSER _CC_NCGL, University of Washington	RCV000038155	SCV000190459	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000183740	SCV000280408	pathogenic	not provided		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.Arg413Stop (c.1237C>T) in the PKP2 gene. This variant has been reported in 6 unrelated individuals with ARVC (Unsoeld et al 2006, Syrris et al 2006, Wlodarska et al 2008, denHan et al 2009, Fressart et al 2010). Unsoeld et al reported a large family with 10 affected individuals all of which are genotype positive for the variant. Within this family there are 5 cases of sudden cardiac death at an early age. A majority of the deaths occurred during physical activity. The authors suggested there was a gender specific penetrance; they report all males with the variant showed symptoms while only 30 % of females with the variant exhibited symptoms. This is a nonsense variant where an Arginine codon is replaced with a Stop codon. Nonsense and splicing variants in PKP2 are the most frequent cause of ARVC. This particular variant is predicted to cause a truncated plakophilin-2 protein with the last 8 of 10 residue repeats missing from the final protein. Unsoeld et al (2009) created a mouse model overexpressing the p.Arg413Stop variant and recapitulated the morphological and electrophysiological phenotype. Syrris et al (2006) report the absence of the variant in 400 ethnically diverse controls. Wlodarska et al (2008) report not seeing the variant in 200 controls and Fressat et al (2010) did not observe the variant in 600 controls. Kapplinger et al (2011) sequenced the ARVC genes (including PKP2) in 427 presumably healthy controls of various ethnicities and did not report this variant. Thus in total the variant was not present in 1627 presumably healthy controls of mixed ancestry.