ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.521G>T (p.Arg174Leu)

dbSNP: rs199472697
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182080 SCV000234383 pathogenic not provided 2024-03-19 criteria provided, single submitter clinical testing Functional studies showed this variant results in trafficking defects and significantly reduced of channel function (PMID: 29532034, 30571187); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21956039, 29532034, 30571187)
Labcorp Genetics (formerly Invitae), Labcorp RCV001852299 SCV002308494 likely pathogenic Long QT syndrome 2023-08-03 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 174 of the KCNQ1 protein (p.Arg174Leu). This missense change has been observed in individual(s) with long-QT syndrome (PMID: 21956039). ClinVar contains an entry for this variant (Variation ID: 200814). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 29532034, 30571187). This variant disrupts the p.Arg174 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9386136, 14998624, 23130128, 23392653, 29532034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes RCV003319329 SCV004024214 pathogenic Long QT syndrome 1 2023-08-01 criteria provided, single submitter clinical testing

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