Submissions for variant NM_000218.3(KCNQ1):c.1046C>G (p.Ser349Trp)

dbSNP: rs199472765

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182330	SCV000234633	pathogenic	not provided	2016-10-14	criteria provided, single submitter	clinical testing	The S349W mutation was first identified in one individual diagnosed with LQTS (Splawski I et al., 2000) and subsequently identified in 15 individuals from 3 families enrolled in the International LQTS Registry (Horr S et al., 2011). The individuals from this registry who harbored the S349W mutation appeared to experience more cardiac events than individuals who harbored other haploinsufficient mutations, despite having a normal ECG during baseline examination. In vitro functional studies showed S349W had a relatively mild effect on the ion channel current but a pronounced effect on channel activation (Horr S et al., 2011). S349W was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. S349W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Missense mutations in this same residue (S349P) and in nearby residues (G345R, G345E, G345V, G350R, G350V, F351S) have been reported in association with LQTS, supporting the functional importance of this region of the protein. The variant is found in KCNQ1 panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377773	SCV001575195	pathogenic	Long QT syndrome	2024-03-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 349 of the KCNQ1 protein (p.Ser349Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 20662986, 22539601; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 52942). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 20662986). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182330	SCV002103234	likely pathogenic	not provided	2021-07-28	criteria provided, single submitter	clinical testing	PP1, PP3, PM2, PS3_supporting, PS4_moderate
Ambry Genetics	RCV003162396	SCV003900188	likely pathogenic	Cardiovascular phenotype	2023-02-07	criteria provided, single submitter	clinical testing	The p.S349W variant (also known as c.1046C>G), located in coding exon 8 of the KCNQ1 gene, results from a C to G substitution at nucleotide position 1046. The serine at codon 349 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals from long QT syndrome cohorts (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Gemma LW et al. J Cardiovasc Electrophysiol, 2011 Oct;22:1141-6; Jons C et al. Sci Transl Med, 2011 Mar;3:76ra28; Stattin EL et al. BMC Cardiovasc Disord, 2012 Oct;12:95). It has also been identified likely in trans with a KCNQ1 pathogenic variant in an individual diagnosed with Jervell and Lange-Nielsen syndrome (Winbo A et al. Europace, 2012 Dec;14:1799-806). Functional studies suggest this variant may result in deficient protein function (Horr S et al. J Cardiovasc Electrophysiol, 2011 Feb;22:193-200). 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000182330	SCV005198549	pathogenic	not provided	2022-10-27	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057538	SCV000089057	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:10973849;PMID:11668638;PMID:14678125;PMID:15840476;PMID:20662986;PMID:17999538;PMID:17470695;PMID:22539601). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.