ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464070 SCV000543459 likely pathogenic Long QT syndrome 2020-06-08 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). This variant has been observed in individuals affected with long QT syndrome (PMID: 26066609, Invitae). ClinVar contains an entry for this variant (Variation ID: 234996). 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 and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000617874 SCV000737441 uncertain significance Cardiovascular phenotype 2019-10-24 criteria provided, single submitter clinical testing The p.L602P variant (also known as c.1805T>C), located in coding exon 7 of the KCNH2 gene, results from a T to C substitution at nucleotide position 1805. The leucine at codon 602 is replaced by proline, an amino acid with similar properties, and is located in the transmembrane-spanning S5/pore region. This alteration has been detected in an individual reported to have QT syndrome (LQTS); however, clinical details were limited (Steffensen AB et al. Sci Rep. 2015;5:10009). This amino acid position is not well conserved in available vertebrate species, and proline is the reference amino acid in other 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.
GeneDx RCV001546262 SCV001765753 uncertain significance not provided 2019-09-12 criteria provided, single submitter clinical testing Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 234996; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26066609, 19841300)
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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