Submissions for variant NM_000218.3(KCNQ1):c.553G>C (p.Val185Leu)

dbSNP: rs749351255

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001348284	SCV001542581	uncertain significance	Long QT syndrome	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 185 of the KCNQ1 protein (p.Val185Leu). This variant is present in population databases (rs749351255, gnomAD 0.02%). 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: 1044083). 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 expected to disrupt KCNQ1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV001841213	SCV002052517	uncertain significance	Cardiac arrhythmia	2021-04-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine 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). 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 9/249674 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.
Ambry Genetics	RCV002350645	SCV002648139	uncertain significance	Cardiovascular phenotype	2021-04-27	criteria provided, single submitter	clinical testing	The p.V185L variant (also known as c.553G>C), located in coding exon 3 of the KCNQ1 gene, results from a G to C substitution at nucleotide position 553. The valine at codon 185 is replaced by leucine, an amino acid with highly similar properties, and is located in the S2/S3 transmembrance-spanning region of the protein. This amino acid position is highly 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.