KCNE3

protein-coding

potassium voltage-gated channel subfamily E regulatory subunit 3, the group of Potassium voltage-gated channel regulatory subunits

Gene summary

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, isk-related subfamily. This member is a type I membrane protein, and a beta subunit that assembles with a potassium channel alpha-subunit to modulate the gating kinetics and enhance stability of the multimeric complex. This gene is prominently expressed in the kidney. A missense mutation in this gene is associated with hypokalemic periodic paralysis. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005472.5

Inheritance

ClinVar variants

U:66B:36

Top phenotype

Brugada syndrome 6

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr11:74,454,841-74,467,729

External References & Databases

Ensembl (ENSG00000175538)

Transcript & Mutation Effects

hg38 • Region Span ~12.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Brugada syndrome 6NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0013145

Submitter: Ambry Genetics

Brugada syndrome 6LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013145

Submitter: Genomics England PanelApp

Brugada syndrome 6NO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0013145

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Brugada syndrome 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013145

Submitter: Labcorp Genetics (formerly Invitae)

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: ClinGen

*KCNE3* encodes an auxiliary beta subunit (potassium voltage-gated channel subfamily E regulatory subunit 3) that interacts with the alpha subunits of voltage-gated potassium channels by modulating gating kinetics and enhancing stability. *KCNE3* expression is observed in several human tissue types, including cardiac tissue (Lundquist et al., 15698834). *KCNE3* was originally classified as “disputed” for Brugada syndrome by the ClinGen Brugada Syndrome Gene Curation Expert Panel in 2017. Contemporary data demonstrate that all key published variants now have population frequencies too high to be considered autosomal dominant causes of Brugada syndrome. *KCNE3* was first reported in relation to Brugada syndrome in 2008 by Delpón et al., who identified a missense variant (c.296G>A, p.Arg99His) in a 36 year old male proband with Brugada syndrome (PMID: 19122847). This variant was also identified in a 45 year old male with Brugada syndrome by Jeong et al., 2024. Nakajima et al. identified missense variant (c.10A>G, p.Thr4Ala) in a 55 year old male proband with Brugada syndrome (PMID: 22987075). The same variant was reported in a single proband in a retrospective review of 71 sudden death cases, although this proband was also found to carry a *KCNE3* variant (Oshima et al. PMID: 28747690). Campuzano et al. identified a missense variant (c.248G>A, p.Arg83His) in a SIDS case with negative autopsy results (PMID: 25016126). Although the focus of this curation is the asserted relationship between *KCNE3* and Brugada syndrome, additional publications suggesting a relationship between *KCNE3* variants and hypertrophic cardiomyopathy, long QT syndrome, and atrial fibrillation were identified and briefly reviewed (PMID: 21967835, PMID: 19306396, PMID: 18209471, PMID: 16313760). The variants identified in these publications were determined to have population frequencies too high to be considered monogenic causes for the associated conditions. *KCNE3* and its association with Brugada syndrome was evaluated by the Hereditary Cardiovascular GCEP on July 22, 2025. Since its original curation in 2017, there has been no additional convincing evidence published to support this relationship. The classification of *KCNE3* and Brugada syndrome remains disputed.

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: G2P

Brugada syndrome 6NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0013145

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Brugada syndrome 6AD

Manifestation: Cardiovascular

Intervention: Cardiovascular; Pharmacogenomic

Rationale: Surveillance with approximately yearly EKG and medical interventions, including daily quinidine for prevention (though treatment of asymptomatic individuals is controversial), ICD placement in individuals with previous cardiac arrest/syncope, and isoproterenol for electrical storms, may be beneficial; Certain agents should be avoided, including medications such as certain anesthetics, antidepressants, and antipsychotics, and care should be taken in the instance of high fever

Refs: 12414843; 14504341; 15037716; 15212652; 19122847; 19306396; 19606473; 20301690; 22397033; 22987075

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNE3 variants in ClinVar

13 Conditions Cataloged

Cardiovascular phenotypeTotal: 84

Brugada syndrome 6Total: 67

not providedTotal: 11

not specifiedTotal: 11

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalitiesTotal: 2

KCNE3-related disorderTotal: 2

Long QT syndromeTotal: 2

Prolonged QT intervalTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005472.5. 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				20 clinvar	1 clinvar	21
missense			59 clinvar	14 clinvar		73
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift			5 clinvar	1 clinvar		6
splice donor/acceptor (+/-2bp)						0
Total	0	0	66	35	1	102

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005472.5	RefSeq	NP_005463.1	1	MANE Select
ENST00000310128.9	Ensembl	ENSP00000310557.4	1	MANE Select
ENST00000525550.1	Ensembl	ENSP00000433633.1	1	Standard
ENST00000525550.2	Ensembl	ENSP00000433633.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein digestion and absorption - Homo sapiens (human)
Antiarrhythmic Pathway, Pharmacodynamics
TYROBP Causal Network
Phase 2 - plateau phase
Phase 3 - rapid repolarisation

Biological Process

regulation of ventricular cardiac muscle cell membrane repolarization
ventricular cardiac muscle cell action potential
membrane repolarization during action potential
regulation of heart rate by cardiac conduction
potassium ion export across plasma membrane

Molecular Function

delayed rectifier potassium channel activity
protein binding
potassium channel regulator activity
ion channel binding
voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization

Cellular Component

cytoplasm
plasma membrane
voltage-gated potassium channel complex
dendrite
vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000310128
Coding exons: 1
Length: 12889
Individuals with no LoFs: 125695
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125703
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.238	62	67.5	0.918	0.00000422	668
Missense (PolyPhen)		19	23.551	0.80676		256
Synonymous	0.548	21	24.4	0.859	0.00000123	218
Loss of Function	1.19	0	1.65	0.00	6.88e-8	23

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel complex. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 (PubMed:12954870). Associated with KCNC4/Kv3.4 is proposed to form the subthreshold voltage-gated potassium channel in skeletal muscle and to establish the resting membrane potential (RMP) in muscle cells. Associated with KCNQ1/KCLQT1 may form the intestinal cAMP-stimulated potassium channel involved in chloride secretion that produces a current with nearly instantaneous activation with a linear current-voltage relationship. {ECO:0000250|UniProtKB:Q9JJV7, ECO:0000269|PubMed:10646604, ECO:0000269|PubMed:12954870}.;

Recessive Scores

pRec: 0.127

Intolerance Scores

LoFtool: 0.219
RVIS EVS: 0.19
RVIS percentile EVS: 66.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.821

Gene Damage Prediction

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