ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2332A>G (p.Ile778Val) (rs145324631)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208084 SCV000264146 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-11-04 criteria provided, single submitter clinical testing
Invitae RCV000464399 SCV000545243 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-04-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 822 of the PKP2 protein (p.Ile822Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs145324631, ExAC 0.01%) but has not been reported in the literature in individuals with a PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 188664). 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 C15"). The valine 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000168939 SCV000565378 uncertain significance not provided 2018-10-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PKP2 gene. The I822V variant has not been published as pathogenic or been reported as benign to our knowledge. I822V has been identified both independently of and in conjunction with additional cardiogenetic variants in multiple other individuals referred for cardiac genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The I822V variant is observed in 8/126690 (0.006%) alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). The I822V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Illumina Clinical Services Laboratory,Illumina RCV000464399 SCV001272953 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.
Color RCV001183988 SCV001349850 uncertain significance Cardiomyopathy 2019-08-02 criteria provided, single submitter clinical testing

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