ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.235C>T (p.Arg79Ter) (rs121434420)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246785 SCV000318240 pathogenic Cardiovascular phenotype 2017-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000007146 SCV000733170 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000183722 SCV000860205 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing
GeneDx RCV000183722 SCV000236200 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing The R79X variant in the PKP2 gene has been reported previously in multiple individuals with ARVC (Gerull et al., 2004; Dalal et al., 2006; van Tintelen et al., 2006; den Haan et al., 2009; Christensen et al., 2010; Klauke et al., 2010; van der Zwaag et al., 2010; Bao et al., 2013; Zhou et al., 2015; Walsh et al., 2017). Additionally, R79X has been observed in several unrelated individuals tested for ARVC at GeneDx. The R79X variant has been shown to segregate with ARVC in multiple relatives from several families, as reported by van Tintelen et al. (2006) and van der Zwaag et al. (2010) and observed at GeneDx. Moreover, R79X is not observed in large population cohorts (Lek et al., 2016). Functional analysis of this nonsense variant showed that R79X reduces the expression level of plakophilin and alters desmosomal protein-protein interactions (Joshi-Mukherjee et al., 2008; Rasmussen et al., 2014). This variant is classified as a pathogenic variant in ClinVar by at least three other laboratories (ClinVar SCV000061874.4, SCV000288604.3, SCV000318240.2; Landrum et al., 2016). We interpret R79X as a pathogenic variant.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000007146 SCV000743461 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2014-10-08 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000007146 SCV000731253 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-11-28 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000007146 SCV000840033 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 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.
Integrated Genetics/Laboratory Corporation of America RCV000780608 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.
Invitae RCV000007146 SCV000288604 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-12-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 79 (p.Arg79*) of the PKP2 gene. It is expected to result in an absent or disrupted protein product. Reduction of PKP2 mRNA and protein was observed in cells from an individual with this PKP2 variant (PMID: 24704780). Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853). This particular variant has been reported in the literature in multiple individuals and families affected with arrhythmogenic right ventricular cardiomyopathy (ARVC), and is clearly defined as an ARVC causative allele (PMID: 19955750, 15489853, 21301620, 21606396). ClinVar contains an entry for this variant (Variation ID: 6754). Experimental studies have shown that this nonsense change causes the protein encoded by PKP2 to fail to localize to sites of cell-cell contact and reduces its interaction with the connexin 43 protein in vitro which in turn was expressed at reduced levels (PMID: 19084810). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211843 SCV000061874 pathogenic Arrhythmogenic right ventricular cardiomyopathy 2017-09-22 criteria provided, single submitter clinical testing The p.Arg79X variant in PKP2 has been previously identified in >15 individuals w ith ARVC and segregated with disease in >15 affected individuals from >5 familie s (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 v ariant has been identified in 1/111652 European chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121434420). Th is 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 stud ies support that this variant results in reduced PKP2 expression (Joshi-Mukherje e 2008). Heterozygous loss of PKP2 function is an established disease mechanism in individuals with ARVC. In summary, this variant meets criteria to be classifi ed as pathogenic for ARVC in an autosomal dominant manner. ACMG/AMP Criteria app lied: PVS1, PS4, PP1_Strong, PM2.
OMIM RCV000007146 SCV000027342 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 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.

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