ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.2020G>A (p.Val674Met) (rs143038626)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544505 SCV000638878 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-11-22 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 674 of the PKP2 protein (p.Val674Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs143038626, ExAC 0.05%). This variant has not been reported in the literature in individuals with PKP2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 RCV000620648 SCV000737474 uncertain significance Cardiovascular phenotype 2018-10-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825436 SCV000966734 uncertain significance not specified 2019-03-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Val674Met variant in PKP2 has not been previously reported in individuals with cardiomyopathy but has been reported by other clinical laboratories in ClinVar (Variation ID 464418). In addition, it has been identified in 0.05% (13/24958) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide evidence for or against impact to the protein. In summary, while the clinical significance of the p.Val674Met variant is uncertain, its frequency in the general population suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_supporting.
Illumina Clinical Services Laboratory,Illumina RCV000544505 SCV001269279 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-01-12 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.
Color RCV001184765 SCV001350826 uncertain significance Cardiomyopathy 2020-02-19 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256702 SCV001433105 uncertain significance not provided 2019-12-06 criteria provided, single submitter clinical testing

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