ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.895C>T (p.Arg299Cys) (rs564987195)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625285 SCV000744710 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-05-31 criteria provided, single submitter clinical testing
Invitae RCV000625285 SCV000818713 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 299 of the PKP2 protein (p.Arg299Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs564987195, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyophathy (ARVC) (PMID: 24125834). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786190 SCV000924898 uncertain significance not provided 2018-02-06 no assertion criteria provided provider interpretation p.Arg299Cys (c.895C>T) in exon 3 of the PKP2 gene (NM_004572.3) Chromosome location 12:33030919 G / A Based on the information reviewed below, including the lack of case data, prevalence in population databases, and the fact that this variant is the default amino acid in more than one mammalian species, we classify it as a Variant of Uncertain Significance (VUS), Probably Benign. ? This variant has been reported in one Chinese individual affected with arrhythmogenic right ventricular cardiomyopathy (Bao et al. 2013; PMID: 24125834). There is no published segregation data. Of note, splice-site-disrupting, frameshift, or other “radical” variants are more likely than missense variants such as this one to be disease-causing in PKP2. Walsh et al. (2017) report that for rare protein-altering variants (ExAC MAF < 0.01%), 26% of ARVC patients (cohort N=361) have a truncating variant in the PKP2 gene, compared to 0.1% of the individuals in ExAC (N=60,000). For non-truncating variants in the PKP2 gene, by contrast, there is essentially no excess among patients: they are present in 1.7% of ARVC patients and 1.3% of individuals in ExAC. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with particular caution (Kapplinger et al. 2011). This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine capable of forming disulfide bridges. Arginine at this location is poorly conserved across the vertebrate species for which we have data. Cysteine is in fact the default amino acid in at least 2 mammalian species. There are no Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of missense change. According to the Invitae report, in silico algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in at least two mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 18 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 12 South Asians (for the highest allele frequency: 0.04%), and 6 non-Finnish Europeans. Overall minor allele frequency (MAF) = 0.007%. Invitae reports that this variant has an allele count higher than expected for a pathogenic variant. Of note, Whffin et al. (2017) have proposed that variants with a MAF of over 0.009% are unlikely to be pathogenic for ARVC. Other variants at the same codon are also present in gnomAD: p.Arg299Leu (2 individuals), p.Arg299His (3 individuals), p.Arg299Gly (1 individual). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Our patient’s ancestry is from Russia.

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