Submissions for variant NM_000218.3(KCNQ1):c.1246G>A (p.Val416Met)

gnomAD frequency: 0.00001  dbSNP: rs777546418

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841083	SCV001356746	uncertain significance	Cardiac arrhythmia	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 416 of the KCNQ1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNQ1-related disorders in the literature. This variant has been identified in 3/251178 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.
All of Us Research Program, National Institutes of Health	RCV004010358	SCV004836407	uncertain significance	Long QT syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 416 of the KCNQ1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV004994308	SCV005608341	uncertain significance	Cardiovascular phenotype	2024-09-27	criteria provided, single submitter	clinical testing	The p.V416M variant (also known as c.1246G>A), located in coding exon 9 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1246. The valine at codon 416 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004010358	SCV005824501	uncertain significance	Long QT syndrome	2024-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 416 of the KCNQ1 protein (p.Val416Met). This variant is present in population databases (rs777546418, gnomAD 0.003%). 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: 926680). 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 expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. 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.