rs199473460

Positions:

• chr11-2572862-T-C
• chr11-2572862-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.797T>C​(p.Leu266Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,461,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 3.78

Genes affected

KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a helix (size 25) in uniprot entity KCNQ1_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_000218.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 11-2572862-T-C is Pathogenic according to our data. Variant chr11-2572862-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572862-T-C is described in Lovd as [Pathogenic]. Variant chr11-2572862-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.797T>C	p.Leu266Pro	missense_variant	6/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.797T>C	p.Leu266Pro	missense_variant	6/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.416T>C	p.Leu139Pro	missense_variant	6/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.536T>C	p.Leu179Pro	missense_variant	7/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-10573T>C		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461486 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000722 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Sep 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 08, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 08, 2015	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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2022	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) -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Long QT syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 24, 2023	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. -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2021

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. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		1.0, 0.99
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473460; hg19: chr11-2594092;