Submissions for variant NM_000218.3(KCNQ1):c.797T>C (p.Leu266Pro)

dbSNP: rs199473460

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046131	SCV000074144	pathogenic	Long QT syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 266 of the KCNQ1 protein (p.Leu266Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or long QT syndrome (PMID: 1467812, 17470695, 17905336, 21118729, 21451124, 22949429). ClinVar contains an entry for this variant (Variation ID: 53108). 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 have shown that this missense change affects KCNQ1 function (PMID: 21451124). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000182116	SCV000234419	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect on channel function (Jons et al., 2011); 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: 14678125, 17470695, 22581653, 10973849, 15840476, 17905336, 19716085, 19841300, 21131640, 23153844, 22949429, 19817925, 21451124, 26318259, 26224781, 25192979, 26743238, 28407228, 28518168, 22456477, 21118729, 27000522, 11668638, 33087929, 34319147)
Ambry Genetics	RCV000250332	SCV000320565	pathogenic	Cardiovascular phenotype	2021-07-29	criteria provided, single submitter	clinical testing	The p.L266P pathogenic mutation (also known as c.797T>C), located in coding exon 6 of the KCNQ1 gene, results from a T to C substitution at nucleotide position 797. The leucine at codon 266 is replaced by proline, an amino acid with similar properties, and is located in the S5 transmembrane spanning region. This mutation has been described as one of the most common causative variants for long QT syndrome (LQTS), having been reported in multiple patients with long QT syndrome (LQTS), numerous patients from LQTS genetic testing cohorts, and patients with Jervell and Lange-Nielsen syndrome who carried a second mutation in KCNQ1 (Splawski I et al. Circulation. 2000;102(10):1178-85; Tester DJ et al. Heart Rhythm. 2005;2(5):507-17; Moss A et al. Circulation. 2007;115(19):2481-9; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Rice KS et al. Heart Rhythm. 2011;8(4):551-4; Whiffin N et al. Genet. Med., 2017 Oct;19:1151-1158). In an in vitro study, this variant disrupted channel function, suggesting an association with increased risk for cardiac events (Jons C et al. Sci Transl Med. 2011;3(76):26ra28). Based on internal structural analysis, this variant is predicted to destabilize the transmembrane S5 helix (Long et al. Nature. 2007;450(7168):376-82). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Gharavi Laboratory, Columbia University	RCV000182116	SCV000809443	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
AiLife Diagnostics, AiLife Diagnostics	RCV000182116	SCV002502756	likely pathogenic	not provided	2021-09-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483053	SCV002777587	likely pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-08-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046131	SCV004030095	pathogenic	Long QT syndrome	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.797T>C (p.Leu266Pro) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 253780 control chromosomes. c.797T>C has been reported in the literature in multiple individuals affected with Long QT Syndrome (Example: Adler_2016, Chung_2007, Kapa_2009, Spawski_2000) . These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating an effect on channel function (Jons_2011). The following publications have been ascertained in the context of this evaluation (PMID: 26743238, 17905336, 21451124, 19841300, 10973849). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182116	SCV004565333	pathogenic	not provided	2023-08-08	criteria provided, single submitter	clinical testing	The KCNQ1 c.797T>C; p.Leu266Pro variant (rs199473460) is reported in multiple individuals and families with long QT syndrome (Cann 2017, Giudicessi 2012, Moss 2007, Splawski 2000, Zareba 2003), and functional studies show this variant has as effect on channel function (Jons 2011). This variant is also reported in ClinVar (Variation ID: 53108). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.941). Based on available information, this variant is considered to be pathogenic. References: Cann F et al. Phenotype-driven molecular autopsy for sudden cardiac death. Clin Genet. 2017 Jan;91(1):22-29. PMID: 27000522. Giudicessi JR et al. Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. PMID: 22949429. Jons C et al. Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients. Sci Transl Med. 2011 Mar 30;3(76):76ra28. PMID: 21451124. Moss AJ et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007 May 15;115(19):2481-9. PMID: 17470695. Splawski I et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5;102(10):1178-85. PMID: 10973849. Zareba W et al. Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. J Cardiovasc Electrophysiol. 2003 Nov;14(11):1149-53. PMID: 14678125.
All of Us Research Program, National Institutes of Health	RCV000046131	SCV004827548	pathogenic	Long QT syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This variant replaces leucine with proline at codon 266 in 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). This variant is found within a highly conserved pore region (a.a. 262-282). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that the variant causes significant potassium current changes in a transfected Xenopus oocyte model (PMID: 21451124). This variant has been reported in almost forty individuals affected with long QT syndrome (PMID: 11668638, 14678125, 17470695, 19841300, 37445499, 36102233) or suspected of having long QT syndrome (PMID: 10973849, 15840476, 17905336, 26743238). This variant has been observed in two siblings with Jervell Lange-Nielsen syndrome in compound heterozygous state with a known pathogenic variant p.Gly269Ser in the same gene (PMID: 21118729). 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 Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000182116	SCV005198544	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057763	SCV000089282	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:17905336;PMID:19716085;PMID:19841300;PMID:17470695). 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	RCV000182116	SCV000280164	likely pathogenic	not provided	2015-04-08	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.Leu266Pro Given the strong case data and absence in controls and individuals who are presumed to not have long QT we consider this variant likely disease causing. The variant has been seen in at least 38 unrelated cases of long QT or likely long QT. There is no segregation data available. The variant was first reported by Splawski et al (2000) in one family with long QT syndrome. No specifics of phenotype or segregation were provided, whoever all subjects had a diagnosis of long QT. Subjects were recruited from North America and Europe. Larsen et al (2001) report this variant in a methods paper, noting samples came from Danish LQTS patients and their family members. There is no overlap in authors between Splawski et al and Larsen et al, however given the vagueness of "European recruitment in Splawski et al it is possible they overlap. The same group as Splawski et al later reported on genotype-phenotype correlations, including subjects with this variant, however it is unclear whether they are all from the same family or multiple families or whether they observed segregation with long QT phenotype (Zareba et al 2003, Moss et al 2007). Ackerman's group observed the variant in four unrelated individuals with long QT or suspected long QT referred to their lab for research-based genetic testing (Tester et al 2005). Skinner's group reported the variant in three unrelated patients with long QT syndrome in New Zealand, all of European descent (Chung et al 2007). The variant was reported in 30 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). We did not do an exhaustive literature search. Zareba et al (2003) note this variant as "pre-pore"/N-terminal region. Chung et al (2007) note it is in the S5 domain. In total the variant has not been seen in 60,794 published controls and individuals from publicly available population datasets. The variant was not observed in the following published control samples: 744 (Tester et al 2005), 50 (Chung et al 2007). There is no variation at codon 266 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent (as of April 8th, 2015).