Submissions for variant NM_000218.3(KCNQ1):c.859G>T (p.Ala287Ser)

dbSNP: rs765665086

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841084	SCV001356752	uncertain significance	Cardiac arrhythmia	2020-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 287 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250332 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862995	SCV002209707	uncertain significance	Long QT syndrome	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 287 of the KCNQ1 protein (p.Ala287Ser). This variant is present in population databases (rs765665086, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 926686). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 28491751). 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.
Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	RCV003319447	SCV004024206	uncertain significance	Long QT syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004033391	SCV005033056	uncertain significance	Cardiovascular phenotype	2023-09-25	criteria provided, single submitter	clinical testing	The p.A287S variant (also known as c.859G>T), located in coding exon 6 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 859. The alanine at codon 287 is replaced by serine, an amino acid with similar properties. This variant has been detected in an individual from a long QT syndrome cohort; however details were limited (Walsh R et al. Genet Med, 2021 Jan;23:47-58). One in vitro functional study indicated this variant may result in a gain of function effect; however, additional evidence is needed to confirm this finding (Rothenberg I et al. HeartRhythm Case Rep, 2016 Nov;2:521-529). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001862995	SCV005426316	uncertain significance	Long QT syndrome	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 287 of the KCNQ1 protein. This variant is found within the highly conserved extracellular linker region (a.a. 283-299). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 32893267). This variant has been identified in 1/250332 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.