Submissions for variant NM_000218.3(KCNQ1):c.776G>T (p.Arg259Leu)

dbSNP: rs199472720

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182114	SCV000234417	pathogenic	not provided	2022-09-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 22949429, 23392653, 31737537, 22456477, 21185501, 25525159, 28483220, 19490272, 25929701, 15466642, 18752142, 19841300, 15840476, 19716085, 26675252)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390400	SCV001592124	pathogenic	Long QT syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 259 of the KCNQ1 protein (p.Arg259Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 15466642, 19490272, 19841300, 23392653, 26675252). ClinVar contains an entry for this variant (Variation ID: 53102). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg259 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11021476, 16922724, 21350584, 23158531, 24291113, 26346102). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002408549	SCV002674911	likely pathogenic	Cardiovascular phenotype	2022-11-30	criteria provided, single submitter	clinical testing	The p.R259L variant (also known as c.776G>T), located in coding exon 5 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 776. The arginine at codon 259 is replaced by leucine, an amino acid with dissimilar properties. This variant has been previously reported in a case indicated as having clinically "definite" long QT syndrome (LQTS), and has also been reported in multiple unrelated individuals referred for long QT syndrome (LQTS) genetic testing, although in some cases clinical details were limited and some reports may overlap (Choi G et al. Circulation. 2004;110(15):2119-24; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Berge KE et al. Scand J Clin Lab Invest. 2008;68(5):362-8; Jons C et al. J Cardiovasc Electrophysiol. 2009;20(8):859-65; Kapa S et al. Circulation. 2009;120(18):1752-60). This variant was also reported in an individual with LQTS who carried a second KCNQ1 alteration (Giudicessi JR et al. Circ Cardiovasc Genet. 2013;6(2):193-200). This variant co-occurred in trans with a second KCNQ1 alteration in an individual with Jervell and Lange-Nielsen syndrome (Torrado M et al. NPJ Genom Med. 2021 Mar;6(1):21). In addition, another alteration affecting this amino acid (p.R259H, c.776G>A) has also been reported in association with LQTS (Millat G et al. Clin Genet. 2006;70(3):214-27). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057757	SCV000089276	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15466642;PMID:15840476;PMID:18752142;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.