KCNQ3
protein-codingpotassium voltage-gated channel subfamily Q member 3, the group of Potassium voltage-gated channels
Gene summary
This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]
- EBN2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~360.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0100062
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
*KCNQ3* encodes the potassium voltage-gated channel, KQT-like subfamily, member 3, which is expressed in the brain and regulates the resting membrane potential and sets the threshold and duration of the action potential in excitable cells (PMID: 33013448). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found differences in molecular mechanism, inheritance pattern, and phenotypic variability for this gene. Therefore, this curation has been split into multiple entities: autosomal dominant self-limited familial neonatal epilepsy (MONDO:0100023; thought to be loss of function), autosomal dominant complex neurodevelopmental disorder (MONDO:0100038; thought to be gain of function), and autosomal recessive developmental and epileptic encephalopathy (MONDO:0100062, mechanism unclear). These split curations have been curated separately by the Epilepsy GCEP and this entry will only cover autosomal dominant complex neurodevelopmental disorder (CND) (MONDO:0100038). *KCNQ3* was first reported in relation to CND in 2012 by Rauch et al. (PMID:23020937) when a missense variant was found in a proband with severe intellectual disability and multifocal epileptic activity. The mechanism of pathogenicity involves gain-of-function missense variants, usually occurring de novo (PMIDs: 31177578, 25740509). Eight missense variants reported in 24 probands across 7 publications (PMIDs: 23020937, 28135719, 31177578, 31238879, 33004838, 33037390, 34356170) were scored in this curation. Several recurrent variants have been identified: four probands carried the variant p.Arg227Gln and three different recurrent amino acid substitutions have been reported in 15 probands for p.Arg230 (p.Arg230Cys, p.Arg230His, p. Arg230Ser). In summary, *KCNQ3* is definitely associated with autosomal dominant complex neurodevelopmental disorder. This was approved by the ClinGen Epilepsy GCEP on 8/1/2023 (SOP v.9).
Inheritance Pattern: AD
Disease ID:MONDO:0007366
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0100023
Submitter: ClinGen
*KCNQ3* encodes the potassium voltage-gated channel, KQT-like subfamily, member 3, which is expressed in the brain and regulates the resting membrane potential and sets the threshold and duration of the action potential in excitable cells (PMID: 33013448). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found differences in molecular mechanism, inheritance pattern, and phenotypic variability for this gene. Therefore, this curation has been split into multiple entities: autosomal dominant self-limited familial neonatal epilepsy (MONDO:0100023; thought to be loss of function), autosomal dominant complex neurodevelopmental disorder (MONDO:0100038; thought to be gain of function), and autosomal recessive developmental and epileptic encephalopathy (MONDO:0100062, mechanism unclear). These split curations have been curated separately by the Epilepsy GCEP and this entry will only cover autosomal dominant self-limited familial neonatal epilepsy (SLFNE) (MONDO:0100023). *KCNQ3* was first reported in relation to SLFNE in 1998 (Charlier et al., PMID:9425900) when a missense variant was found in 13 affected individuals in the same family. The mechanism of pathogenicity involves loss-of-function missense variants, mainly inherited from symptomatic parents. This mechanism has been confirmed with a multitude of functional studies, most using a Xenopus laevis expression system and voltage clamp techniques to discover a reduced expression or impaired function of the potassium channel when a variant is present (PMID: 25524373, 27781029, 9872318, 18625963, 14534157, 33013448). Fifteen missense variants reported in 18 probands across 16 publications (PMIDs: 9425900, 10852552, 14534157, 18249525, 18625963, 23146207, 24375629, 25052858, 25278462, 25524373, 27781029, 27888506, 31302675, 33013448, 34153113, 35384780) were scored in this curation. Of note, case 15 in Sands et al. (PMID:27888506) has a deletion of exons 1-15; because this paper did not provide specific breakpoints, it cannot be formally entered into this curation. However, we have awarded this predicted/proven null variant 1.5 points. Bringing the total genetic evidence, including case level segregation, to 9.4 points. This gene-disease relationship is supported by two papers discussing functional alteration in non-patient cells (PMID: 35857840, 18425618) and an additional paper outlining the protein interactions of *KCNQ3* and *KCNQ2* (PMID: 9677360). In this curation, experimental evidence was awarded 1.5 points. In summary, *KCNQ3* has a moderate association to autosomal dominant self-limited familial neonatal epilepsy (SLFNE).The total number of points for this curation is 9.4 plus 1.5 pts for the multi-exon deletion, bringing our total to 10.9 points.This curation was approved by the ClinGen Epilepsy GCEP on 8/1/2023 (SOP v.9).
Inheritance Pattern: AR
Disease ID:MONDO:0100062
Submitter: ClinGen
*KCNQ3* encodes the potassium voltage-gated channel, KQT-like subfamily, member 3, which is expressed in the brain and regulates the resting membrane potential and sets the threshold and duration of the action potential in excitable cells (PMID: 33013448). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found differences in molecular mechanism, inheritance pattern, and phenotypic variability for this gene. Therefore, this curation has been split into multiple entities: autosomal dominant self-limited familial neonatal epilepsy (MONDO:0100023; thought to be loss of function), autosomal dominant complex neurodevelopmental disorder (MONDO:0100038; thought to be gain of function), and autosomal recessive developmental and epileptic encephalopathy (MONDO:0100062, mechanism unclear). These split curations have been curated separately by the Epilepsy GCEP and this entry will only cover autosomal recessive developmental and epileptic encephalopathy (AR-DEE) (MONDO:0100062). *KCNQ3* was first reported in relation to AR-DEE in 2018 by Kothur et al. (PMID: 29852413) when a homozygous frameshift variant was detected in a male proband with familial neonatal seizures, hypotonia, and severe intellectual disability (ID). Subsequently in 2019, Lauritano et al. (PMID: 31440727) reported a different homozygous frameshift variant detected in a female proband with moderate intellectual disability (ID) and generalized convulsions associated with hypotonia, cyanosis, and clonic movements of the four limbs. Both probands were born to consanguineous parents. Of note, in PMID 29852413, patients in the same family reported clinical heterogeneity characterized by variable degrees of ID and the presentation of seizures. In summary, *KCNQ3* has limited association with autosomal recessive developmental and epileptic encephalopathy. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This was approved by the ClinGen Epilepsy GCEP on 8/1/2023 (SOP v.9).
Inheritance Pattern: AD
Disease ID:MONDO:0007366
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0017615
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007366
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0016027
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KCNQ3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004519.4. 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 | 1 | 9 | 296 | 1 | 307 | |
| missense | 10 | 36 | 574 | 50 | 670 | |
| nonsense | 3 | 5 | 11 | 19 | ||
| start loss | 1 | 1 | ||||
| frameshift | 9 | 5 | 17 | 31 | ||
| splice donor/acceptor (+/-2bp) | 6 | 4 | 10 | |||
| Total | 22 | 53 | 616 | 346 | 1 | 1038 |
Highest pathogenic variant AF is 0.00012466269
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004510.1 | 15 | MANE Select | |
| Ensembl | ENSP00000373648.3 | 15 | MANE Select | |
| RefSeq | NP_001191753.1 | 15 | Standard | |
| Ensembl | ENSP00000428790.1 | 15 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| kcnq3 | Danio rerio | Structure: transmission of nerve impulse Quality: process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cholinergic synapse - Homo sapiens (human)
- Celecoxib Pathway, Pharmacodynamics
- Developmental Biology
- ion channels and their functional role in vascular endothelium
- Neuronal System
Biological Process
- chemical synaptic transmission
- regulation of ion transmembrane transport
- membrane hyperpolarization
- potassium ion transmembrane transport
Molecular Function
- voltage-gated potassium channel activity
- delayed rectifier potassium channel activity
- protein binding
- calmodulin binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- voltage-gated potassium channel complex
- cell surface
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000388996
- Coding exons
- 15
- Length
- 360093
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125748
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.07 | 350 | 477 | 0.734 | 0.0000291 | 5604 |
| Missense (PolyPhen) | 109 | 209.28 | 0.52083 | 2433 | ||
| Synonymous | 0.409 | 193 | 200 | 0.963 | 0.0000129 | 1796 |
| Loss of Function | 4.74 | 8 | 40.5 | 0.197 | 0.00000251 | 451 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Associates with KCNQ2 or KCNQ5 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs. Therefore, it is important in the regulation of neuronal excitability. {ECO:0000269|PubMed:11159685, ECO:0000269|PubMed:14534157, ECO:0000269|PubMed:16319223, ECO:0000269|PubMed:9872318}.;
- Disease
- DISEASE: Seizures, benign familial neonatal 2 (BFNS2) [MIM:121201]: A disorder characterized by clusters of seizures occurring in the first days of life. Most patients have spontaneous remission by 12 months of age and show normal psychomotor development. The disorder is distinguished from benign familial infantile seizures by an earlier age at onset. {ECO:0000269|PubMed:10852552, ECO:0000269|PubMed:14534157, ECO:0000269|PubMed:25982755, ECO:0000269|PubMed:9425900, ECO:0000269|PubMed:9872318}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in KCNQ3 may be involved in epileptic disorders. These are characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system. {ECO:0000269|PubMed:22612257}.;
Recessive Scores
- pRec
- 0.109
Intolerance Scores
- LoFtool
- 0.0830
- RVIS EVS
- -0.33
- RVIS percentile EVS
- 30.82
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.806
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |