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

gnomAD frequency: 0.00004  dbSNP: rs781333509

Total submissions: 3

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001315852	SCV001506445	uncertain significance	Long QT syndrome	2025-01-12	criteria provided, single submitter	clinical testing	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). 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 missense change has been observed in individual(s) with lone atrial fibrillation (PMID: 23710137). ClinVar contains an entry for this variant (Variation ID: 925375). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNQ1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 34930020). 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.
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.