Submissions for variant NM_000218.3(KCNQ1):c.553G>A (p.Val185Met)

gnomAD frequency: 0.00002  dbSNP: rs749351255

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842726	SCV001342643	uncertain significance	Cardiac arrhythmia	2019-06-19	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 185 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 3/249674 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001875885	SCV002119446	uncertain significance	Long QT syndrome	2024-09-16	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 185 of the KCNQ1 protein (p.Val185Met). 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 variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 919842). 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: 36077086). 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.
All of Us Research Program, National Institutes of Health	RCV001875885	SCV004838758	uncertain significance	Long QT syndrome	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 185 of the KCNQ1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant causes an increase of channel current upon co-expression of KCNE2 in CHO cells (PMID: 36077086). This variant has been reported in an individual affected with non-arrhythmic cardiovascular disease (PMID: 31696929), and in three related individuals affected with gingival overgrowth (PMID: 36077086). This variant has been identified in 3/249674 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.