ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.302G>A (p.Arg101His) (rs149542398)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172093 SCV000051041 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038217 SCV000061885 likely benign not specified 2016-01-22 criteria provided, single submitter clinical testing p.Arg101His in exon 2 of PKP2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, the seal and 3 bat species have a histidine (His) at this position despite h igh nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been iden tified in 13/66714 European chromosomes by the Exome Aggregation Consortium (ExA C,; dbSNP rs149542398).
Invitae RCV000230829 SCV000288606 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 101 of the PKP2 protein (p.Arg101His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs149542398, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy, Brugada syndrome and dilated cardiomyopathy (PMID: 20400443, 24503780, 26230511), but also in an unaffected control individual (PMID: 23861362). Additionally, this variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 45076). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The histidine amino acid residue is also 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. 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.
Ambry Genetics RCV000246062 SCV000319173 uncertain significance Cardiovascular phenotype 2019-03-27 criteria provided, single submitter clinical testing Insufficient evidence;In silico models in agreement (benign)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000172093 SCV000885972 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing The p.Arg101His variant (rs149542398) has been observed in several cohorts of cardiomyopathy patients (selected references: Allegue 2015, Fressart 2010, Pugh 2014) and one control cohort (Ng 2013); however, specific clinical information and segregated data were not provided. This variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.034% (identified in 43 out of 126,664 chromosomes). It is also listed in the ClinVar database (Variation ID: 45076). The arginine at codon 101 is weakly conserved considering 8 species (Alamut software v2.9), and computational analyses suggest this does not have a significant effect on PKP2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Arg101His variant cannot be determined with certainty.
Color RCV000777973 SCV000914076 likely benign Cardiomyopathy 2019-11-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172093 SCV001148702 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000230829 SCV001266942 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-11-21 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000777973 SCV001332780 likely benign Cardiomyopathy 2017-11-08 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256846 SCV001433331 uncertain significance Conduction disorder of the heart 2020-04-14 criteria provided, single submitter clinical testing

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