ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1237C>T (p.Arg413Ter) (rs372827156)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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:// 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 2018-12-26 criteria provided, single submitter clinical testing The R413X pathogenic variant in the PKP2 gene has been reported in several individuals in association with ARVC, and has been shown to segregate with ARVC in multiple affected relatives from unrelated families (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). The R413X variant has also been observed in multiple individuals referred for arrhythmia/cardiomyopathy genetic testing at GeneDx, and it is classified as pathogenic or likely pathogenic in ClinVar by other clinical laboratories (SCV000061821.4, SCV000220018.2, SCV000545238.2; Landrum et al., 2016). R413X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. mRNA expression studies performed by Unsoeld et al. (2009) suggest that R413X causes protein truncation. Multiple other downstream nonsense variants in the PKP2 gene have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Finally, the R413X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Invitae RCV000471559 SCV000545238 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-10-17 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. This variant is present in population databases (rs372827156, ExAC 0.01%). This particular variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy and to segregate with the disease in one family (PMID: 20400443, 20857253, 21606390, 24967631). ClinVar contains an entry for this variant (Variation ID: 45016). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000588929 SCV000698461 pathogenic Arrhythmogenic right ventricular dysplasia/cardiomyopathy 2016-10-31 criteria provided, single submitter clinical testing Variant summary: The PKP2 c.1237C>T (p.Arg413X) variant results in a premature termination codon, predicted to cause a truncated or absent PKP2 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 (e.g.c.1912C>T/p.Gln638X, c.2013delC/p.Lys672fsX12). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/122408 control chromosomes at a frequency of 0.0000163, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKP2 variant (0.0006502). This variant has been reported in numerous ARVD patients with evidence of co-segregation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000619035 SCV000734891 pathogenic Cardiovascular phenotype 2017-08-04 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Illumina Clinical Services Laboratory,Illumina RCV000471559 SCV000915591 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 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 cardiomyopathy, type 9 2020-01-14 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170218 SCV001332775 pathogenic Cardiomyopathy 2018-07-05 criteria provided, single submitter clinical testing
Color RCV001170218 SCV001342800 pathogenic Cardiomyopathy 2018-12-04 criteria provided, single submitter clinical testing
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.

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