ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1951C>T (p.Arg651Cys) (rs199583774)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766577 SCV000236247 uncertain significance not provided 2018-08-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PKP2 gene. The R695C variant has been reported in one family with ARVC (Adler et al., 2016) and in one patient with sudden infant death (SIDS) (Neubauer et al., 2017); however, additional clinical information was not provided in either report. The R695C variant is observed in 34/277130 (0.012%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the R695C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000415669 SCV000638879 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 695 of the PKP2 protein (p.Arg695Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199583774, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a family affected with an unspecified inherited cardiac disease (PMID: 26743238). ClinVar contains an entry for this variant (Variation ID: 45056). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on PKP2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000620572 SCV000737866 uncertain significance Cardiovascular phenotype 2017-01-04 criteria provided, single submitter clinical testing Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000766577 SCV001148692 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000415669 SCV001266716 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171160 SCV001333845 uncertain significance Cardiomyopathy 2017-11-14 criteria provided, single submitter clinical testing
Color RCV001171160 SCV001357607 uncertain significance Cardiomyopathy 2019-06-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038196 SCV000061863 uncertain significance not specified 2008-12-30 no assertion criteria provided clinical testing
Blueprint Genetics RCV000157416 SCV000207156 uncertain significance Primary dilated cardiomyopathy 2014-09-29 no assertion criteria provided clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000415669 SCV000493778 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2016-01-27 no assertion criteria provided clinical testing

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