KCNH1

protein-coding

potassium voltage-gated channel subfamily H member 1, the group of Potassium voltage-gated channels|PAS domain containing

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, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

MANE transcript

NM_172362.3

Inheritance

AD, AR

ClinVar variants

P:32U:397B:332

Top phenotype

Temple-Baraitser syndrome; Zimmermann-Laband syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr1:210,676,823-211,134,165

External References & Databases

Ensembl (ENSG00000143473)

Transcript & Mutation Effects

hg38 • Region Span ~457.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

KCNH1 associated disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100485

Submitter: Illumina

Temple-Baraitser syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012735

Submitter: Labcorp Genetics (formerly Invitae)

Temple-Baraitser syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012735

Submitter: Orphanet

KCNH1 associated disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100485

Submitter: ClinGen

*KCNH1* (also referred to as hEAG/EAG1/Kv10.1) encodes a voltage gated potassium channel with high expression levels in CNS. Heterozygous de novo rare missense variants in *KCNH1* are reported in individuals with a clinical diagnosis of Temple-Baraitser syndrome whose features include ID, epilepsy, hypoplasia/aplasia of the nails of the thumb and great toe (PMID: 25420144), Zimmermann-Laband syndrome which is characterized by ID, hypoplasia of nails and terminal phalanges, facial dysmorphism, gingival enlargement, hypertrichosis (PMID: 25915598), and in individuals with non-syndromic ID with or without epilepsy (PMID: 33811134). Due to phenotypic overlap of these clinical entities, shared missense variants observed in these conditions and a common molecular mechanism of the identified missense changes (gain of function), these entities represent a phenotypic continuum and have been curated under the encompassing term of “KCNH1-associated disorders” (PMIDs: 26264464, 27282200, 25420144, 25915598, 33811134, 33594261, 33494179, 26818738, 32956079). Evidence supporting this gene-disease relationship includes case-level data and functional studies on the missense variants. Notably, experimental data using patient cells and knock-in animal models with disease causing variants are lacking for *KCNH1*. There are roughly 30 affected individuals with *KCNH1* variants reported in the literature to date (PMIDs: 33594261, 33494179, 33811134). Nearly all of the cases had de novo missense variants; however, there are at least 2 reports of inheritance of this disorder from mothers who showed low level somatic mosaicism for the *KCNH1* variant (PMID: 25420144). Two independent studies assessed a handful of *KCNH1* missense variants seen in affected individuals by in vitro patch-clamp studies and were shown to cause gain of function effects (PMIDs: 25420144, 25915598). The postulated disease mechanism for KCNH1 missense variants is through gain of function, though in a single case, an inherited nonsense variant (exon 8 of 11) was reported in an individual with seizures and in other asymptomatic family members suggesting non-penetrance (PMID: 33494179). This case was not scored. For experimental evidence and animal models for *KCNH1*, there are only loss of function-based mouse and Zebrafish models reported (PMIDs: 22927438, 22927438). Since this is not consistent with the postulated molecular mechanism of the missense *KCNH1* variants seen in the affected individuals, these studies were not scored. *KCNH1* is definitively associated with KCNH1-associated disorders. This classification has been approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 5, 2022 (SOP Version 8).

Zimmermann-Laband syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000200

Submitter: Orphanet

Temple-Baraitser syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012735

Submitter: G2P

Temple-Baraitser syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012735

Submitter: Ambry Genetics

Zimmermann-Laband syndrome 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0024526

Submitter: Ambry Genetics

KCNH1 associated disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100485

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Temple-Baraitser syndrome; Zimmermann-Laband syndrome 1AD/AR

Manifestation: Craniofacial; Dental; Dermatologic; Gastrointestinal; Musculoskeletal; 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

Refs: 18203178; 20683999; 23994350; 24357613; 25420144; 25915598

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNH1 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 798

Inborn genetic diseasesTotal: 79

not specifiedTotal: 76

KCNH1-related disorderTotal: 51

Temple-Baraitser syndromeTotal: 35

Zimmermann-Laband syndrome 1Total: 34

KCNH1 associated disorderTotal: 4

Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_172362.3. 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			2 clinvar	223 clinvar	6 clinvar	231
missense	14 clinvar	18 clinvar	367 clinvar	83 clinvar	16 clinvar	498
nonsense			10 clinvar	2 clinvar		12
start loss						0
frameshift			13 clinvar	2 clinvar		15
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	14	18	397	310	22	761

Highest pathogenic variant AF is 0.0000041340477

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_172362.3	RefSeq	NP_758872.1	11	MANE Select
ENST00000271751.10	Ensembl	ENSP00000271751.4	11	MANE Select
NM_002238.4	RefSeq	NP_002229.1	11	Standard
ENST00000367007.5	Ensembl	ENSP00000355974.5	12	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kcnh1b	Danio rerio	Structure: somite border Quality: inconspicuous abnormal

Gene / Model

Organism

Observed Phenotype

kcnh1b

Danio rerio

Structure: somite border

Quality: inconspicuous

abnormal

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

startle response
potassium ion transport
myoblast fusion
regulation of ion transmembrane transport
regulation of cell population proliferation

Molecular Function

voltage-gated potassium channel activity
delayed rectifier potassium channel activity
protein binding
calmodulin binding
protein kinase binding

Cellular Component

nuclear inner membrane
plasma membrane
integral component of plasma membrane
voltage-gated potassium channel complex
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000271751
Coding exons: 11
Length: 450903
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125748
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.82	317	574	0.552	0.0000333	6524
Missense (PolyPhen)		50	179.06	0.27923		2042
Synonymous	0.143	229	232	0.988	0.0000144	1958
Loss of Function	4.45	8	37.3	0.214	0.00000193	432

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel (PubMed:9738473, PubMed:11943152, PubMed:10880439, PubMed:22732247, PubMed:25556795, PubMed:27325704, PubMed:27005320, PubMed:27618660). Channel properties are modulated by subunit assembly (PubMed:11943152). Mediates IK(NI) current in myoblasts (PubMed:9738473). Involved in the regulation of cell proliferation and differentiation, in particular adipogenic and osteogenic differentiation in bone marrow-derived mesenchymal stem cells (MSCs) (PubMed:23881642). {ECO:0000269|PubMed:10880439, ECO:0000269|PubMed:11943152, ECO:0000269|PubMed:22732247, ECO:0000269|PubMed:23881642, ECO:0000269|PubMed:25556795, ECO:0000269|PubMed:27005320, ECO:0000269|PubMed:27325704, ECO:0000269|PubMed:27618660, ECO:0000269|PubMed:9738473}.;
Disease: DISEASE: Temple-Baraitser syndrome (TMBTS) [MIM:611816]: A developmental disorder characterized by intellectual disability, epilepsy, hypoplasia or aplasia of the thumb and great toe nails, and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. Some patients show facial dysmorphism. {ECO:0000269|PubMed:25420144}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Zimmermann-Laband syndrome 1 (ZLS1) [MIM:135500]: A disorder characterized by gingival fibromatosis, dysplastic or absent nails, finger abnormalities, hepatosplenomegaly, and abnormalities of the cartilage of the nose and/or ears. {ECO:0000269|PubMed:25915598}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.215

Intolerance Scores

LoFtool: 0.0368
RVIS EVS: -1.09
RVIS percentile EVS: 7.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.849

Gene Damage Prediction

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