ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.2750C>T (p.Pro917Leu) (rs76420733)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181888 SCV000234191 likely benign not specified 2015-11-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000181888 SCV000539444 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 probands but also found in controls - Multiple reports question pathogenicity; ClinVar: 2 VUS
Invitae RCV000699321 SCV000828026 uncertain significance Long QT syndrome 2019-02-21 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 917 of the KCNH2 protein (p.Pro917Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with LongQT syndrome (PMID: 11854117, 10973849), as well as unaffected controls (19841300, 17161064). ClinVar contains an entry for this variant (Variation ID: 67432). Experimental studies in zebrafish have shown that this missense change restores repolarization activity of KCNH2 channel to near wild type levels (PMID: 23303164). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000058158 SCV001155306 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001160952 SCV001322791 uncertain significance Long QT syndrome 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Health, Inc RCV001182258 SCV001347648 uncertain significance Arrhythmia 2019-12-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000181888 SCV001372241 uncertain significance not specified 2020-06-15 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.2750C>T (p.Pro917Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 124454 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in KCNH2 causing Arrhythmia (8e-05 vs 0.0001), allowing no conclusion about variant significance. c.2750C>T has been reported in the literature in individuals affected with Arrhythmia (Splawski_2000, Moss_2002, Shimizu_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Jou_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058158 SCV000089678 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:10973849;PMID:11854117;PMID:14661677;PMID:17161064;PMID:19841300).

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