ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1993C>T (p.Leu665Phe) (rs397517018)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766578 SCV000236249 uncertain significance not provided 2014-12-19 criteria provided, single submitter clinical testing p.Leu709Phe (CTC>TTC): c.2125 C>T in exon 10 of the PKP2 gene (NM_004572.3). The L709F variant in the PKP2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The L709F 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 L709 residue is conserved in mammals and in silico analysis predicts L709F is damaging to the protein structure/function. However, L709F is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. Definitive missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot definitively determine if L709F is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV000550372 SCV000638881 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-10-22 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 709 of the PKP2 protein (p.Leu709Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 45060). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038200 SCV000061867 uncertain significance not specified 2009-06-08 no assertion criteria provided clinical testing

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