ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2141G>A (p.Arg714Gln)

gnomAD frequency: 0.00004  dbSNP: rs397517020
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000038202 SCV000061870 uncertain significance not specified 2014-07-03 criteria provided, single submitter clinical testing The Arg758Gln variant in PKP2 has not been reported in any other families with c ardiomyopathy and was absent from large populations studies. Computational predi ction tools and conservation analysis suggest that this variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. In summary, the clinical significance of the Arg758Gln variant is uncertain .
GeneDx RCV000766581 SCV000236254 uncertain significance not provided 2021-09-10 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 45062; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918)
Invitae RCV000640007 SCV000761594 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2022-10-05 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 758 of the PKP2 protein (p.Arg758Gln). This variant is present in population databases (rs397517020, gnomAD 0.02%). 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: 45062). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Color Diagnostics, LLC DBA Color Health RCV001178856 SCV001343409 uncertain significance Cardiomyopathy 2023-09-27 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 758 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 12/282796 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.
Ambry Genetics RCV003162333 SCV003866198 uncertain significance Cardiovascular phenotype 2023-01-10 criteria provided, single submitter clinical testing The p.R758Q variant (also known as c.2273G>A), located in coding exon 11 of the PKP2 gene, results from a G to A substitution at nucleotide position 2273. The arginine at codon 758 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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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