Submissions for variant NM_000218.3(KCNQ1):c.674C>T (p.Ser225Leu)

gnomAD frequency: 0.00001  dbSNP: rs199473456

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046103	SCV000074116	pathogenic	Long QT syndrome	2024-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 225 of the KCNQ1 protein (p.Ser225Leu). This variant is present in population databases (rs199473456, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 9927399, 10973849, 15840476, 17470695, 19716085, 22727609, 22949429, 23130128, 24606995). ClinVar contains an entry for this variant (Variation ID: 53083). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 11087258, 19590188, 21451124, 22456477). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000057730	SCV000731736	likely pathogenic	Congenital long QT syndrome	2023-10-27	criteria provided, single submitter	clinical testing	The p.Ser225Leu variant in KCNQ1 has been reported in >15 individuals with long QT syndrome (LQTS) or referred for LQTS genetic testing (Priori 1999 PMID: 9927399, Splawski 2000 PMID: 10973849, Tester 2005 PMID: 15840476, Kapplinger 2009 PMID: 19716085, Andrsova 2012 PMID: 22727609, Giudicessi 2012 PMID: 22949429, Christiansen 2014 PMID: 24606995). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 53083) and has been identified in 0.003% (1/30612) of South Asian and 0.001% (2/112392) European chromosomes by gnomAD (http://gnomad.broadinstitute.org/, v.2.1.1). In vitro functional studies provide some evidence that the p.Ser225Leu variant may impact protein function, potentially through a dominant negative mechanism (Bianchi 2000 PMID: 11087258, Henrion 2009 PMID: 19590188, Barsheshet 2012 PMID: 22456477) and computational prediction tools and conservation analysis suggest that the p.Ser225Leu variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Ser225Leu variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PS3_Supporting, PP3.
Color Diagnostics, LLC DBA Color Health	RCV001841649	SCV001357885	likely pathogenic	Cardiac arrhythmia	2019-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 225 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown this variant has a dominant-negative effect on potassium channel current and changes the activation and deactivation rates of the channel (PMID: 11087258, 19590188, 21451124, 22456477). This variant has been reported in many individuals affected with long QT syndrome or referred for long QT syndrome genetic testing (PMID: 9927399, 10973849, 14678125, 15466642, 15840476, 17470695, 19716085, 19841300, 21451124, 22456477, 22727609, 22949429, 23130128, 24606995, 29925740). This variant has been identified in 3/248308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256914	SCV001433432	pathogenic	Long QT syndrome 1	2019-05-02	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001256914	SCV001435329	pathogenic	Long QT syndrome 1	2020-06-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362677	SCV002663609	likely pathogenic	Cardiovascular phenotype	2024-02-26	criteria provided, single submitter	clinical testing	The p.S225L variant (also known as c.674C>T), located in coding exon 4 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 674. The serine at codon 225 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with long QT syndrome (LQTS) (Priori SG et al. Circulation. 1999;99(4):529-33; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Moss AJ et al. Circulation. 2007;115(19):2481-9; Itoh H et al. Heart Rhythm. 2010;7(10):1411-8; Andrsova I et al. J Electrocardiol. 2012;45(6):746-51; Christiansen M et al. BMC Med. Genet. 2014;15:31). This alteration has also been shown to have an impact on protein function (Bianchi L et al. Am. J. Physiol. Heart Circ. Physiol. 2000;279(6):H3003-11; Henrion U et al. Cell. Physiol. Biochem. 2009;24(1-2):11-6; Jons C et al. Sci Transl Med. 2011;3:76ra28; Liin SI et al. Elife. 2016;5:e20272). 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.
Fulgent Genetics, Fulgent Genetics	RCV002504939	SCV002809876	pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-11-23	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335079	SCV004046295	pathogenic	KCNQ1-related disorder		criteria provided, single submitter	clinical testing	This variant has been reported in multiple individuals and families affected with long QT syndrome (PMID: 9927399, 10973849, 15840476, 17470695, 19716085, 22949429, 23130128). Experimental studies have shown that this missense change has a dominant-negative effect on channel activity (PMID: 11087258, 19590188, 21451124, 22456477). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/248308) and thus is presumed to be rare. The c.674C>T (p.Ser225Leu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.674C>T (p.Ser225Leu) variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000046103	SCV005426305	likely pathogenic	Long QT syndrome	2024-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 225 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown this variant has a dominant-negative effect on potassium channel current and changes the activation and deactivation rates of the channel (PMID: 11087258, 19590188, 21451124, 22456477). This variant has been reported in many individuals affected with long QT syndrome or referred for long QT syndrome genetic testing (PMID: 9927399, 10973849, 14678125, 15466642, 15840476, 17470695, 19716085, 19841300, 21451124, 22456477, 22727609, 22949429, 23130128, 24606995, 29925740). This variant has been identified in 3/248308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057730	SCV000089249	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:9927399;PMID:10973849;PMID:14678125;PMID:15466642;PMID:15840476;PMID:19590188;PMID:19716085;PMID:19841300;PMID:17999538;PMID:17470695;PMID:22456477). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000182302	SCV000280160	likely pathogenic	not provided	2014-10-13	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Ser225Leu This variant has been reported in at least 11 unrelated individuals with LQTS and as many as 13 total subjects. There is no segregation data available on the variant. Priori et al (1999) first identified the variant in an Italian family where 1 member had a LQTS diagnosis and 2 first degree relatives were found to be carriers but did not have a clinical diagnosis. Splawski et al (2000) reported 2 families with p.S225L and LQTS. One family is from the US and the other is from Italy, thus we cannot assume that this family is a separate new case from the Priori et al family. Three years later the same author group reports the presence of the variant in 2/294 cases derived from the International Long QT Registry (Zareba et al). Based on the sample source and author group it is highly likely that these 2 cases are the same as the cases in Splawskis paper. Choi et al (2004) report that the variant was identified in 1/388 unrelated patients sent to Mayo for LQTS genetic testing between August 1997 and May 2003. The average QTc of the cohort was 482ms. The individual was a 12 yo male whose arrhythmic event was triggered by swimming. Tester et al (2005) reported the variant in 3/541 unrelated cases sent to Mayo for testing between August 1997 and July 2004. One of these cases likely overlaps with Choi et al. Moss et al (2007) reported the variant in 13/600 individuals with LQT. It cannot be assumed that these 13 subjects are not related. Kapplinger et al (2009) reported 8 unrelated cases with the variant out of 2500 patients referred to Familion for LQTS genetic testing between May 2004 and October 2008. Recently Medlock et al (2012) re-tested all LQTS subjects who were found to be genotype negative in previous studies (n=269) and identified 1 additional new case with p.S225L variant. Thus bringing the total to 11 unrelated cases. The Couderc et al (2012) publication mentions p.S225L variant but the patient population had previously been genotyped thus no new cases can be added. This is a non conservative amino acid change with a polar Serine replaced with a nonpolar Leucine. In silico analysis predict the amino acid replacement to be damaging /possibly damaging to resulting protein function (SIFT/PolyPhen). Additional variants (R231C, R231H) in nearby codons have been reported in association with LQTS thus indicating a functional significance of this region of the KCNQ1 gene. Henrion et al (2009) demonstrated that xenopus oocytes with the p.S225L variant in KCNQ1 had altered voltage dependencies for activation and deactivation compared to wildtype oocytes. Priori et al (1999) did not identify the variant in 100 presumably healthy controls. Kapplinger et al (2009) report that the variant was absent in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). In total the variant is absent if 1400 presumably healthy individuals. The variant is listed in dbSNP with the rs # 199473456; however there is no allele frequency data available. It is not listed in 1000Genomes. There is no variation at codon 225 in the NHLBI ESP, which currently includes variant calls from ~6500 individuals (as of November 29th 2012).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000046103	SCV000804995	likely pathogenic	Long QT syndrome	2016-04-21	no assertion criteria provided	clinical testing