KCNQ1

protein-coding

potassium voltage-gated channel subfamily Q member 1, the group of Potassium voltage-gated channels

Gene summary

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]

Previous symbols:

LQT
KCNA9

MANE transcript

NM_000218.3

Inheritance

AD, AR, Digenic

ClinVar variants

P:618U:769B:479

Top phenotype

Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome 2; Atrial fibrillation, familial 3

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr11:2,444,654-2,849,105

External References & Databases

Ensembl (ENSG00000053918)

Transcript & Mutation Effects

hg38 • Region Span ~404.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

short QT syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: ClinGen

KCNQ1 encodes the alpha subunit of the slowly activating delayed rectifier cardiac potassium channel (Iks). Bellocq et al. were the first to identify a rare KCNQ1 missense variant (p.Val180Leu ClinVar Variation ID# 3148) in a patient with SQTS (PMID 15159330). Subsequently, 9 other probands with SQTS were found to carry another variant (p.Val14Met, ClinVar Variation ID# 67072). Interestingly, all of these 9 cases presented with severe bradycardia in-utero or at birth and in 6 atrial fibrillation was also documented (PMIDs 24818999, 26279191, 16109388, 24380499, 25974115, 28491547). Importantly, in none of the p.Val14Met cases was cardiac arrest or SCD described. In fact, cardiac arrest was described only in the first case described by Bellocq et al. In 4 cases the p.Val14Met variant was demonstrated to be de-novo although paternity was not proven in all. In another 4 cases no other family members were diagnosed and in one family the father of the proband was identified with the p.Val14Met variant and demonstrated a mild phenotype. The fact that almost all genetic evidence was derived from a single variant led the Expert Panel to limit the classification of KCNQ1 as a SQTS-causing gene to “Strong”, despite evidence being reproducible over time.

Jervell and Lange-Nielsen syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0002441

Submitter: ClinGen

The relationship between KCNQ1 and autosomal recessive Jervell and Lange-Nielsen Syndrome (JLNS) was evaluated using the ClinGen Clinical Validity Framework as of 12/11/2017. Variants in KCNQ1 were first reported in humans with this disease as early as 1997 (Neyroud et al., PMID 9020846). At least 11 unique variants (missense, in-frame indel, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data knockout mouse models, rescue in mice, as well as expression of KCNQ1 in the heart and inner ear (PMIDs: 11226272, 11223304, 26084842, 9020846). The mechanism for disease is homozygous LOF of the KCNQ1 gene causes JLNS though alterations have also been shown to cause Romano-Ward Syndrome in an AD manner (PMID: 29037160). Variants in this gene have been reported in at least 9 probands in 9 publications (PMIDs 29037160, 27041150, 9020846, 27868350, 25187895, 24206879). Variants in this gene segregated with disease in 2 additional family members. In summary, KCNQ1 is definitively associated with Jervell and Lange-Nielsen Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 12/19/2017.

long QT syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100316

Submitter: G2P

familial atrial fibrillationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018054

Submitter: Orphanet

short QT syndrome type 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012313

Submitter: G2P

short QT syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: Orphanet

Jervell and Lange-Nielsen syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009078

Submitter: Orphanet

Jervell and Lange-Nielsen syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024540

Submitter: G2P

familial hypertrophic cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

long QT syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: ClinGen

KCNQ1 encodes the alpha subunit of the slowly activating delayed rectifier cardiac potassium channel (Iks). Wang et al. were the first to identify variants in this gene using linkage analysis in families with LQTS (PMID 8528244). An abundance of experimental and genetic evidence, including segregation and case-control data, has accumulated over the decades since this publication to support the association of KCNQ1 with LQTS. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams were reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”

long QT syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100316

Submitter: Labcorp Genetics (formerly Invitae)

hypertrophic cardiomyopathyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

Variants in the *KCNQ1* gene have been reported to cause autosomal dominant hypertrophic cardiomyopathy(HCM) based on case-level data alone in 2016. Previously, only 1 missense variant has been reported in an individual that presented with HCM and long QTc (LQTS) (PMID: 24183960). This individual also carried variants in two other genes associated with HCM. The re-curation of *KCNQ1* presented 1 missense variant (c1781G>A, p.(Arg594Gln) in an individual with HCM and long QTc intervals (Cava et al., 2021 PMID: 33777698). This individual also carries a variant in *TNNI3* (c.592C>G, p.Leu198Val). This variant in *TNNI3* is considered likely pathogenic and segregated in individuals in the family presenting with hypertrophic cardiomyopathy. Variants in *KCNQ1* have been shown to be pathogenic in individuals and families with Long QT. The current ClinGen Clinical Validity Framework is for Mendelian inheritance and does not support classifications for disease in which multiple genes may be contributory. At this time there is no clinical or experimental evidence to support association of *KCNQ1* to HCM pathogenicity. This curation was previously published by the Hypertrophic Cardiomyopathy GCEP in 2017 with a classification of No Known Disease Relationship. At this time, during recuration, the relationship of KCNQ1 with autosomal dominant hypertrophic cardiomyopathy has now been classified as DISPUTED by the Hereditary Cardiovascular Diseases GCEP as of April 13, 2022.

long QT syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100316

Submitter: G2P

atrial fibrillation, familial, 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011857

Submitter: Labcorp Genetics (formerly Invitae)

short QT syndrome type 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012313

Submitter: Labcorp Genetics (formerly Invitae)

Jervell and Lange-Nielsen syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024540

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome 2; Atrial fibrillation, familial 3AD/AR/Digenic

Manifestation: Audiologic/Otolaryngologic; Cardiovascular

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: Medical/surgicalmanagement (eg, ICD placement, antiarhythymognic medications) may help prevent/decrease severe sequelae, though cardiac transplantion has been necessary for some individuals; For individuals with JLNS1, recognition and prompt treatment of hearing loss may be beneficial

Comments: The age of onset of clinical manifestations may be highly variable; The condition can manifest with hearing loss in JLNS1 in addition to cardiac manifestations; Digenic inheritance (eg, with KCNH2) has been described

Refs: 13435203; 4393533; 112730; 7365362; 6991948; 7471361; 1884444; 8892796; 8872472; 8528244; 9020846; 9164812; 9702906; 9593563; 9753711; 10086971; 10077519; 10220144; 10973849; 11140949; 11289718; 11479253; 11433047; 12522251; 12736279; 15159330; 15051636; 16132053; 15890322; 15840476; 16461811; 16922724; 18580685; 19261104; 20301308; 20301579; 21185499; 21952006; 22293141; 22456477; 22708720; 22727609; 22882672; 22885918; 23000022

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNQ1 variants in ClinVar

46 Conditions Cataloged

Long QT syndromeTotal: 1608

not providedTotal: 1294

Cardiovascular phenotypeTotal: 738

Cardiac arrhythmiaTotal: 630

Long QT syndrome 1Total: 401

Congenital long QT syndromeTotal: 304

not specifiedTotal: 199

Jervell and Lange-Nielsen syndrome 1Total: 185

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000218.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	3 clinvar	2 clinvar	11 clinvar	442 clinvar	6 clinvar	464
missense	66 clinvar	251 clinvar	729 clinvar	24 clinvar	5 clinvar	1075
nonsense	42 clinvar	25 clinvar	2 clinvar	1 clinvar		70
start loss	2 clinvar		2 clinvar			4
frameshift	96 clinvar	60 clinvar	21 clinvar			177
splice donor/acceptor (+/-2bp)	22 clinvar	49 clinvar	4 clinvar	1 clinvar		76
Total	231	387	769	468	11	1866

Highest pathogenic variant AF is 0.00021995207

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000218.3	RefSeq	NP_000209.2	16	MANE Select
ENST00000155840.12	Ensembl	ENSP00000155840.2	16	MANE Select
NM_001406836.1	RefSeq	NP_001393765.1	15	Standard
NM_001406837.1	RefSeq	NP_001393766.1	17	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kcnq1	Danio rerio	Structure: whole organism Quality: edematous abnormal

Gene / Model

Organism

Observed Phenotype

kcnq1

Danio rerio

Structure: whole organism

Quality: edematous

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein digestion and absorption - Homo sapiens (human)
Gastric acid secretion - Homo sapiens (human)
Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
Vibrio cholerae infection - Homo sapiens (human)
Pancreatic secretion - Homo sapiens (human)

Biological Process

regulation of gene expression by genetic imprinting
sensory perception of sound
regulation of heart contraction
positive regulation of heart rate
gene silencing

Molecular Function

voltage-gated potassium channel activity
delayed rectifier potassium channel activity
protein binding
calmodulin binding
phosphatidylinositol-4,5-bisphosphate binding

Cellular Component

cytoplasm
lysosome
early endosome
late endosome
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000155840
Coding exons: 16
Length: 404426
Individuals with no LoFs: 125664
Homozygous LoFs: 0
Heterozygous LoFs: 84
Defined: 125748
p: 0.000334

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.83	295	398	0.742	0.0000272	4283
Missense (PolyPhen)		97	175.73	0.55199		1739
Synonymous	-1.73	206	177	1.17	0.0000131	1420
Loss of Function	2.37	17	31.3	0.543	0.00000152	351

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00052	0.00052	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00033	0.00033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Potassium channel that plays an important role in a number of tissues, including heart, inner ear, stomach and colon (By similarity) (PubMed:10646604). Associates with KCNE beta subunits that modulates current kinetics (By similarity) (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505, PubMed:19687231). Induces a voltage-dependent by rapidly activating and slowly deactivating potassium-selective outward current (By similarity) (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505). Promotes also a delayed voltage activated potassium current showing outward rectification characteristic (By similarity). During beta- adrenergic receptor stimulation participates in cardiac repolarization by associating with KCNE1 to form the I(Ks) cardiac potassium current that increases the amplitude and slows down the activation kinetics of outward potassium current I(Ks) (By similarity) (PubMed:9312006, PubMed:9108097, PubMed:8900283, PubMed:10646604, PubMed:11101505). Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current (PubMed:10713961). When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions (PubMed:10646604). This interaction with KCNE3 is reduced by 17beta-estradiol, resulting in the reduction of currents (By similarity). During conditions of increased substrate load, maintains the driving force for proximal tubular and intestinal sodium ions absorption, gastric acid secretion, and cAMP-induced jejunal chloride ions secretion (By similarity). Allows the provision of potassium ions to the luminal membrane of the secretory canaliculus in the resting state as well as during stimulated acid secretion (By similarity). When associated with KCNE2, forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (PubMed:11101505). When associated with KCNE4, inhibits voltage-gated potassium channel activity (PubMed:19687231). When associated with KCNE5, this complex only conducts current upon strong and continued depolarization (PubMed:12324418). Also forms a heterotetramer with KCNQ5; has a voltage-gated potassium channel activity (PubMed:24855057). Binds with phosphatidylinositol 4,5- bisphosphate (PubMed:25037568). {ECO:0000250|UniProtKB:P97414, ECO:0000250|UniProtKB:Q9Z0N7, ECO:0000269|PubMed:10646604, ECO:0000269|PubMed:10713961, ECO:0000269|PubMed:11101505, ECO:0000269|PubMed:12324418, ECO:0000269|PubMed:19687231, ECO:0000269|PubMed:24855057, ECO:0000269|PubMed:25037568, ECO:0000269|PubMed:8900283, ECO:0000269|PubMed:9108097, ECO:0000269|PubMed:9312006}.;
Disease: DISEASE: Long QT syndrome 1 (LQT1) [MIM:192500]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. {ECO:0000269|PubMed:10024302, ECO:0000269|PubMed:10220144, ECO:0000269|PubMed:10220146, ECO:0000269|PubMed:10367071, ECO:0000269|PubMed:10409658, ECO:0000269|PubMed:10482963, ECO:0000269|PubMed:10728423, ECO:0000269|PubMed:10973849, ECO:0000269|PubMed:11799244, ECO:0000269|PubMed:12442276, ECO:0000269|PubMed:15840476, ECO:0000269|PubMed:16414944, ECO:0000269|PubMed:16922724, ECO:0000269|PubMed:18165683, ECO:0000269|PubMed:18400097, ECO:0000269|PubMed:19540844, ECO:0000269|PubMed:19716085, ECO:0000269|PubMed:19808498, ECO:0000269|PubMed:21241800, ECO:0000269|PubMed:24184248, ECO:0000269|PubMed:24269949, ECO:0000269|PubMed:24713462, ECO:0000269|PubMed:25037568, ECO:0000269|PubMed:25139741, ECO:0000269|PubMed:25705178, ECO:0000269|PubMed:8528244, ECO:0000269|PubMed:8818942, ECO:0000269|PubMed:8872472, ECO:0000269|PubMed:9024139, ECO:0000269|PubMed:9272155, ECO:0000269|PubMed:9302275, ECO:0000269|PubMed:9312006, ECO:0000269|PubMed:9323054, ECO:0000269|PubMed:9386136, ECO:0000269|PubMed:9482580, ECO:0000269|PubMed:9570196, ECO:0000269|PubMed:9641694, ECO:0000269|PubMed:9693036, ECO:0000269|PubMed:9702906, ECO:0000269|PubMed:9799083, ECO:0000269|PubMed:9927399, ECO:0000269|Ref.31}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Jervell and Lange-Nielsen syndrome 1 (JLNS1) [MIM:220400]: An autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death. {ECO:0000269|PubMed:10090886, ECO:0000269|PubMed:10728423, ECO:0000269|PubMed:18400097, ECO:0000269|PubMed:18441444, ECO:0000269|PubMed:25705178, ECO:0000269|PubMed:9781056}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrial fibrillation, familial, 3 (ATFB3) [MIM:607554]: An autosomal dominant form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:12522251}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short QT syndrome 2 (SQT2) [MIM:609621]: A heart disorder characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. It causes syncope and sudden death. {ECO:0000269|PubMed:15159330}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:18711366, ECO:0000269|PubMed:18711367, ECO:0000269|PubMed:24390345}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.337

Intolerance Scores

LoFtool: 0.00344
RVIS EVS: -0.69
RVIS percentile EVS: 15.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.683

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium