Submissions for variant NM_000218.3(KCNQ1):c.1201C>T (p.Arg401Trp)

gnomAD frequency: 0.00007  dbSNP: rs766616232

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726985	SCV000234620	uncertain significance	not provided	2022-08-03	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533)
Eurofins Ntd Llc (ga)	RCV000726985	SCV000704695	uncertain significance	not provided	2016-12-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000182317	SCV000712091	uncertain significance	not specified	2016-05-27	criteria provided, single submitter	clinical testing	The p.Arg401Trp variant in KCNQ1 has not been previously reported in individuals with hearing loss, long QT syndrome, or Jervell and Lange-Nielsen syndrome. It has been reported in one individual in the ClinVar database by a single laborato ry (http://www.ncbi.nlm.nih.gov/clinvar; Accession ID RCV000182317.1); however c linical and genetic findings were not provided. This variant has also been ident ified in 4/11572 Latino chromosomes by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org; dbSNP rs766616232); though this frequency is not high enough to rule out a pathogenic role. Computational prediction tools and co nservation analyses suggest an impact to the protein; however this data is not s ufficient to determine pathogenicity. In summary, the clinical significance of t he p.Arg401Trp variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706581	SCV000835640	uncertain significance	Long QT syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 401 of the KCNQ1 protein (p.Arg401Trp). This variant is present in population databases (rs766616232, gnomAD 0.04%). 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: 200903). 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) has been performed at Invitae 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. 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	RCV001842879	SCV001345200	uncertain significance	Cardiac arrhythmia	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 401 of the KCNQ1 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. 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 20/282708 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002345632	SCV002650529	uncertain significance	Cardiovascular phenotype	2023-11-13	criteria provided, single submitter	clinical testing	The p.R401W variant (also known as c.1201C>T), located in coding exon 9 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1201. The arginine at codon 401 is replaced by tryptophan, an amino acid with dissimilar properties. 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	RCV000706581	SCV004836403	uncertain significance	Long QT syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 401 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). 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 20/282708 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.