ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.176G>A (p.Gly59Asp) (rs794728568)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000801452 SCV000941228 likely pathogenic Long QT syndrome 2019-01-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 186 of the KCNQ1 protein (p.Gly186Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with long QT syndrome in families (PMID: 27485560) and has been reported in an individual affected with this disease (PMID: 26669661). This variant has been observed in a homozygous individual affected with Jervell and Lange-Nielsen syndrome (PMID: 27041150). ClinVar contains an entry for this variant (Variation ID: 207967). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The observation of one or more missense substitutions at this codon (p.Gly186Asp and p.Gly186Arg) in affected individuals suggests that this may be a clinically significant residue (PMID: 27485560, 27041150, 22949429). 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825589 SCV000966931 likely pathogenic Congenital long QT syndrome 2018-05-04 criteria provided, single submitter clinical testing The p.Gly186Asp variant in KCNQ1 has been reported in the heterozygous state in 2 individuals with long QT syndrome (LQTS) and in the homozygous state in 1 indi vidual with Jervell and Lange-Nielsen syndrome (Vyas 2016a, Vyas 2016b, Itoh 201 6). Additionally, the variant segregated with prolonged QT interval in 5 individ uals from 2 families (Vyas 2016a, Vyas 2016b), and was absent from large populat ion studies. Computational prediction tools and conservation analysis suggest th at the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Finally, several variants at the same positi on have been reported in individuals with LQTS (ClinVar variation IDs: 432149, 2 00894, 53065, 67082); however, their clinical significance is unknown due to lim ited available data. In summary, although additional studies are required to ful ly establish its clinical significance, the p.Gly186Asp variant is likely pathog enic. ACMG/AMP Criteria applied: PM2, PP1_Moderate, PP3, PS4_Supporting.
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000234798 SCV000240217 pathogenic Long QT syndrome 1 2013-01-01 no assertion criteria provided research

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