ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1558A>G (p.Ile520Val) (rs763749576)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183745 SCV000236226 uncertain significance not provided 2014-07-18 criteria provided, single submitter clinical testing p.Ile520Val (ATA>GTA): c.1558 A>G in exon 7 of the PKP2 gene (NM_004572.3). The I520V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I520V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not well conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. However, the I520V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, a missense mutation in a nearby residue (T526A) has been reported in association with Brugada syndrome, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000548873 SCV000378455 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.
Invitae RCV000548873 SCV000638867 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 520 of the PKP2 protein (p.Ile520Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs763749576, ExAC 0.02%) but has not been reported in the literature in individuals with a PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 201986). 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 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on 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.
Color RCV000777781 SCV000913756 uncertain significance Cardiomyopathy 2019-04-16 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000777781 SCV001332771 likely benign Cardiomyopathy 2018-03-15 criteria provided, single submitter clinical testing

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