ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1805T>C (p.Leu602Pro) (rs876661348)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464070 SCV000543459 uncertain significance Long QT syndrome 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 602 of the KCNH2 protein (p.Leu602Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 234996). This variant identified in the KCNH2 gene is located in the transmembrane spanning S5/pore region of the resulting protein (PMID: 19841300, 25348405), but it is unclear how this variant impacts the function of this protein. 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect 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.
Ambry Genetics RCV000617874 SCV000737441 uncertain significance Cardiovascular phenotype 2017-12-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223929 SCV000280120 uncertain significance not specified 2013-12-31 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Leu602Pro Based on the evidence reviewed below, we classify this variant as a variant of uncertain significance (VUS). The Leu602Pro variant in the KCNH2 gene is novel, and has not been previously reported as a disease-causing mutation nor as a benign polymorphism to our knowledge (after searches of PubMed and Google). Variation at several nearby residues has been associated with LQT2: I593R, I593T, I593G, I593X, P596L, P596R, G601S, G604S, D609N, D609H, D609G, Y611H, Y611X, V612L (UniProtKB; IRCCS Fondazione Salvatore Maugeri database). This is a conservative amino acid change, resulting in the replacement of a nonpolar leucine with a nonpolar proline. The leucine at this location varies in 9 of 32 mammalian species sequenced, and proline is the normal amino acid in stickleback fish. The adjacent residues similarly vary across species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign”. In total the variant has not been seen in >5330 individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals. There is no variation at this codon listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm), as of May 13, 2012.

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