ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1429A>G (p.Thr477Ala)

gnomAD frequency: 0.00001  dbSNP: rs775192286
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001178317 SCV001342714 uncertain significance Cardiomyopathy 2023-07-28 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine at codon 521 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/251284 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001875893 SCV002301984 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2023-08-10 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 521 of the PKP2 protein (p.Thr521Ala). This variant is present in population databases (rs775192286, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 919896). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 RCV003380857 SCV004097968 uncertain significance Cardiovascular phenotype 2023-07-24 criteria provided, single submitter clinical testing The p.T521A variant (also known as c.1561A>G), located in coding exon 7 of the PKP2 gene, results from an A to G substitution at nucleotide position 1561. The threonine at codon 521 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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