ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2141G>A (p.Arg714Gln) (rs397517020)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2016-06-08 criteria provided, single submitter clinical testing The R758Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant is classified in ClinVar as a variant of uncertain significance by an outside clinical laboratory (Landrum et al., 2014). This 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. The R758Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating this region of the gene is not known to harbor disease-causing variants. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000640007 SCV000761594 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 758 of the PKP2 protein (p.Arg758Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs397517020, ExAC 0.01%). This variant has not been reported in the literature in individuals with PKP2-related disease. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV001178856 SCV001343409 uncertain significance Cardiomyopathy 2019-05-21 criteria provided, single submitter clinical testing

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