KCNH5

protein-coding

potassium voltage-gated channel subfamily H member 5, the group of Potassium voltage-gated channels|PAS domain containing

Gene summary

This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

MANE transcript

NM_139318.5

Inheritance

ClinVar variants

P:11U:436B:309

Top phenotype

Developmental and epileptic encephalopathy 112

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr14:62,699,464-63,102,037

External References & Databases

Ensembl (ENSG00000140015)

Transcript & Mutation Effects

hg38 • Region Span ~402.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neonatal/infantile epilepsy syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100022

Submitter: ClinGen

Variants in *KCNH5* were first reported in an individual with mild motor delay, severe language delay, and epileptic encephalopathy in 2013 (Veeramah et al., PMID: 23647072). Since that time, numerous other individuals with variants in this gene have been reported with features such as intellectual disability, language and developmental delays, and a variety of seizure types. While severity of intellectual disability and developmental delays have been reported to vary across probands, seizures onset in the first year of life across all cases that were reviewed. For this reason, the Epilepsy GCEP has decided to curate this information under the disease term neonatal/infantile epilepsy syndrome (MONDO:0100022). Seven missense variants were reported in 19 probands across four publications (PMIDs: 23647072, 32725632, 35874597, 36307226) and one splice site in one proband (PMID:35874597). Two recurrent missense variants, p.Arg327His and p.Arg333His, were recorded in 10 and 4 patients respectively. Most of the observed variants were characterized as de novo in the probands, although there is one case of inheritance from an affected mother. Of note, genotype-phenotype correlations were described in one paper (PMID:36307226). Functional studies for one recurrent missense variant, p.Arg327His, demonstrate a gain of function effect, though these types of studies have not been performed to confirm the mechanism of other variants. The gene-disease relationship is further supported by animal model and rescue studies (PMID:31728858). Additional experimental evidence is also available in the literature (PMID: 32222671). In summary, there is definitive evidence to support the relationship between *KCNH5* and autosomal dominant neonatal/infantile epilepsy syndrome (MONDO:0100022). This has been repeatedly demonstrated and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on November 15, 2022 (SOP Version 9). As of August 24, 2026, this record underwent administrative updates to change the disease name to neonatal/infantile epilepsy syndrome from infantile-onset epilepsy, as this term has been obsoleted in MONDO. No new evidence has been reviewed or added, and the classification remains the same.

developmental and epileptic encephalopathy 112STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0957812

Submitter: PanelApp Australia

developmental and epileptic encephalopathy 112STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0957812

Submitter: G2P

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 112AD

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

Comments: As with other forms of epilepsy, optimal seizure control is advantageous, and genetic diagnosis may aid with medication selection

Refs: 23647072; 32725632; 34136434; 35874597; 36307226

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNH5 variants in ClinVar

10 Conditions Cataloged

Early-infantile DEETotal: 736

not providedTotal: 95

Inborn genetic diseasesTotal: 93

not specifiedTotal: 22

Developmental and epileptic encephalopathy 112Total: 21

KCNH5-related disorderTotal: 16

Developmental and epileptic encephalopathyTotal: 14

Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regressionTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_139318.5. 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			5 clinvar	227 clinvar	5 clinvar	237
missense	5 clinvar	6 clinvar	399 clinvar	45 clinvar	27 clinvar	482
nonsense			14 clinvar	4 clinvar		18
start loss						0
frameshift			14 clinvar	1 clinvar		15
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	5	6	436	277	32	756

Highest pathogenic variant AF is 0.0000020522166

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_139318.5	RefSeq	NP_647479.2	11	MANE Select
ENST00000322893.12	Ensembl	ENSP00000321427.7	11	MANE Select
NM_172375.3	RefSeq	NP_758963.1	10	Standard
ENST00000394968.2	Ensembl	ENSP00000378419.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuronal System
Voltage gated Potassium channels
Potassium Channels

Biological Process

regulation of G2/M transition of mitotic cell cycle
regulation of ion transmembrane transport
regulation of membrane potential
potassium ion transmembrane transport

Molecular Function

voltage-gated potassium channel activity
calmodulin binding
ion channel binding
protein heterodimerization activity

Cellular Component

plasma membrane
integral component of plasma membrane
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000322893
Coding exons: 11
Length: 395469
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125748
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.51	390	557	0.701	0.0000306	6509
Missense (PolyPhen)		127	243.38	0.52181		2886
Synonymous	0.326	209	215	0.972	0.0000126	1904
Loss of Function	4.47	12	44.0	0.273	0.00000254	505

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00019	0.00014	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits a non-inactivating outward rectifying current. Channel properties may be modulated by cAMP and subunit assembly.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.0324
RVIS EVS: -1.46
RVIS percentile EVS: 3.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.792

Gene Damage Prediction

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