ClinVar Miner

Submissions for variant NM_000218.3(KCNQ1):c.1945G>A (p.Asp649Asn)

gnomAD frequency: 0.00004  dbSNP: rs781333509
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001840994 SCV001353993 likely benign Cardiac arrhythmia 2019-09-04 criteria provided, single submitter clinical testing
Invitae RCV001315852 SCV001506445 uncertain significance Long QT syndrome 2023-03-07 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 34930020). 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 not expected to disrupt KCNQ1 protein function. ClinVar contains an entry for this variant (Variation ID: 925375). This missense change has been observed in individual(s) with lone atrial fibrillation (PMID: 23710137). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 649 of the KCNQ1 protein (p.Asp649Asn).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824929 SCV002074309 uncertain significance not specified 2022-12-12 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.1945G>A (p.Asp649Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 186858 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1945G>A has been reported in the literature in a study of individuals affected with lone atrial fibrillation as well as unaffected controls (example, Chu_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia/Long QT syndrome. One functional study assessed in vitro electrophysiology for the variant compared to wild-type and found the variant to have near normal in vitro function (Glazer_2022). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign/likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.

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