ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1307C>T (p.Thr436Met) (rs199472901)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000631634 SCV000752717 uncertain significance Long QT syndrome 2017-11-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 436 of the KCNH2 protein (p.Thr436Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199472901, ExAC 0.01%). This variant has been reported in several individuals affected with long QT syndrome (PMID: 10973849, 9927399, Invitae). ClinVar contains an entry for this variant (Variation ID: 67184). 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. Experimental studies disagree regarding the effect of this missense change on channel function (PMID: 26129877, 16432067, 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.
Color RCV001188913 SCV001356090 uncertain significance Arrhythmia 2020-04-14 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057891 SCV000089411 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:9927399;PMID:11854117;PMID:16432067). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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