Submissions for variant NM_000218.3(KCNQ1):c.1097G>T (p.Arg366Leu)

dbSNP: rs199473410

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001544877	SCV001764096	likely pathogenic	not provided	2020-01-13	criteria provided, single submitter	clinical testing	Reported in a patient with an inherited arrhythmia syndrome (Bennett et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31737537, 31535183)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002032550	SCV002255767	pathogenic	Long QT syndrome	2023-10-03	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 366 of the KCNQ1 protein (p.Arg366Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 31535183; Invitae). ClinVar contains an entry for this variant (Variation ID: 1185948). 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. This variant disrupts the Arg366 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14678125, 15935335, 19934648, 23158531, 23861489, 26669661). 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	RCV003298922	SCV004007861	likely pathogenic	Cardiovascular phenotype	2023-03-27	criteria provided, single submitter	clinical testing	The p.R366L variant (also known as c.1097G>T), located in coding exon 8 of the KCNQ1 gene, results from a G to T substitution at nucleotide position 1097. The arginine at codon 366 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in subjects with long QT syndrome (LQTS) (Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Bennett JS et al. Pediatr Cardiol, 2019 Dec;40:1679-1687). Two other alterations at the same codon, p.R366W (c.1096C>T) and p.R366Q (c.1097G>A), have also been described in association with LQTS (Splawski I et al. Genomics. 1998;51(1):86-97; Jiménez-Jáimez J et al. Heart, 2015 Aug;101:1232, 1239). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003591880	SCV004358407	likely pathogenic	Cardiac arrhythmia	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 366 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 been reported in individuals affected with or suspected of having long QT syndrome (PMID: 31535183, 31737537). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg366Trp and p.Arg366Gln, are known to be pathogenic (Clinvar variation ID 52955, 52956), indicating that arginine at this position is important for KCNQ1 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.