Submissions for variant NM_001005242.3(PKP2):c.2071C>T (p.Arg691Ter)

dbSNP: rs121434421

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211738	SCV000205873	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2018-02-26	criteria provided, single submitter	clinical testing	The p.Arg735X variant in PKP2 has been reported in 7 individuals with clinical f eatures of ARVC and segregated with disease in 3 affected relatives (Gerull 2004 , Bao 2013, Alcalde 2014, LMM data). This variant has been identified in 1/30780 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs121434421) and has been reported in ClinVar (Vari ation ID 6755). This nonsense variant leads to a premature termination codon at position 735, which is predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the PKP2 gene is an established disease mechanism in ARVC. Transgenic mice expressing p.Arg735X mutant protein in cardiac tissue res ulted in exercise-dependent ARVC phenotype (Cruz 2015). In summary, this variant meets criteria to be classified as pathogenic for ARVC in an autosomal dominant manner based. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1; PS3_Supp orting.
Invitae	RCV000007147	SCV000545246	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg735*) 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, 23911551). This variant is present in population databases (rs121434421, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with arrythmogenic ventricular cardiomyopathy (ARVC) (PMID: 15489853, 24125834, 24967631). ClinVar contains an entry for this variant (Variation ID: 6755). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001557815	SCV001779650	pathogenic	not provided	2022-05-13	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; Functional studies show that over-expression of human p.(R735*) in mice induced an exercise-dependent ARVC phenotype (Cruz et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32466575, 24125834, 25525159, 17363426, 18382419, 24832006, 24967631, 28008009, 30385303, 28471438, 29178656, 29606362, 30790397, 31737537, 32268277, 32372669, 31386562, 31402444, 33232181, 15489853, 25857910)
CeGaT Center for Human Genetics Tuebingen	RCV001557815	SCV002545017	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	PKP2: PVS1, PM2, PS4:Moderate, PS3:Supporting
Ambry Genetics	RCV002426495	SCV002727510	pathogenic	Cardiovascular phenotype	2022-04-04	criteria provided, single submitter	clinical testing	The p.R735* pathogenic mutation (also known as c.2203C>T), located in coding exon 11 of the PKP2 gene, results from a C to T substitution at nucleotide position 2203. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been reported in subjects with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Gerull B et al. Nat. Genet., 2004 Nov;36:1162-4; Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Alcalde M et al. PLoS ONE, 2014 Jun;9:e100560; Ruiz Salas A et al. Rev Esp Cardiol (Engl Ed), 2018 Dec;71:1018-1026). Transgenic mice with cardiac-specific expression of this variant developed exercise-dependent right ventricular dysfunction resembling ARVC (Cruz FM et al. J. Am. Coll. Cardiol., 2015 Apr;65:1438-50). 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.
OMIM	RCV000007147	SCV000027343	pathogenic	Arrhythmogenic right ventricular dysplasia 9	2004-11-01	no assertion criteria provided	literature only
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000211738	SCV001430828	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-06-26	no assertion criteria provided	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us.