ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.554C>T (p.Thr185Ile) (rs120074182)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182136 SCV000234439 pathogenic not provided 2020-03-31 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate a damaging effect as the T312I variant results in an inactive potassium channel (Shalaby et al., 1997; Westenskow et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15051636, 22456477, 14678125, 27114410, 15466642, 22949429, 9323054, 23153844, 19815527, 19841300, 19862833, 26669661, 17470695, 19716085, 10973849, 15840476, 25734225, 8528244, 20368164)
Color Health, Inc RCV001184216 SCV001350156 likely pathogenic Arrhythmia 2019-11-08 criteria provided, single submitter clinical testing
Invitae RCV001386969 SCV001587425 pathogenic Long QT syndrome 2020-03-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 312 of the KCNQ1 protein (p.Thr312Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (rs120074182, ExAC no frequency). This variant has been reported in numerous individuals and families affected with long QT syndrome (PMID: 8528244, 10973849, 15051636, 22727609, 25294783, 21451124, Invitae). This variant is also known as p.Thr183Ile and p.Thr311Ile in the literature. ClinVar contains an entry for this variant (Variation ID: 3116). Experimental studies have shown that this missense change has a dominant negative effect on KCNQ1 activity (PMID: 9323054, 15051636, 22456477), and an equivalent missense change in a transgenic mouse model recapitulates features of KCNQ1-associated long QT syndrome (PMID: 15498462, 20368164). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003263 SCV000023421 pathogenic Long QT syndrome 1 1996-01-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057808 SCV000089328 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:8528244;PMID:9323054;PMID:10973849;PMID:14678125;PMID:15051636;PMID:15466642;PMID:15840476;PMID:19716085;PMID:19841300;PMID:20368164;PMID:17470695;PMID:22456477). 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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