GeneBe

HCN1

protein-coding

hyperpolarization activated cyclic nucleotide gated potassium channel 1, the group of Cyclic nucleotide gated channels

Gene summary

The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. This channel may act as a receptor for sour tastes. [provided by RefSeq, Oct 2011]

Previous symbols:
  • BCNG1

MANE transcript

NM_021072.4

Inheritance

AD

ClinVar variants

P:49U:566B:382

Top phenotype

Developmental and epileptic encephalopathy 24; Generalized epilepsy with febrile seizures plus, type 10

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr5:45,254,948-45,696,498

External References & Databases

Ensembl (ENSG00000164588)NCBI Gene (348980)OMIM (602780)HGNC:4845GenCCUniProt (O60741)AlphaFoldClinVar (HCN1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~441.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

generalized epilepsy with febrile seizures plus, type 10STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032777

Submitter: PanelApp Australia

generalized epilepsy with febrile seizures plusSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018214

Submitter: Orphanet

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

generalized epilepsy with febrile seizures plusDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018214

Submitter: ClinGen

*HCN1* was first reported in relation to patients with autosomal dominant epilepsy in 2014 (Nava et al., PMID: 24747641). Since then, there have been assertions for both a relationship between *HCN1* and autosomal dominant developmental and epileptic encephalopathy (DEE), and between *HCN1* and autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have not found evidence of differences in disease mechanism between probands diagnosed with either GEFS+ or DEE; further, there are currently no discernable genotype-phenotype correlations, and no known differences in disease mechanism between these two entities (PMID: 34310985). The Epilepsy GCEP has therefore lumped these cases into one curation for autosomal dominant GEFS+ (MONDO:0018214), including probands with presentations of infantile epileptic encephalopathy on the severe end of the spectrum, as well as individuals with milder presentations. Twenty missense variants reported in 26 probands in four publications are included in this curation (PMIDs: 27864847, 30351409, 24747641, 35359652). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Both purported loss of function and gain of function variants in *HCN1* have been identified in patients with autosomal dominant GEFS+ (PMID: 34310985). This gene-disease relationship is also supported by mouse models (PMIDs: 33822003, 35972069). In summary, there is definitive evidence supporting the relationship between *HCN1* and autosomal dominant GEFS+. 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 Epilepsy GCEP on the meeting date January 3, 2023 (SOP Version 9).

developmental and epileptic encephalopathy, 24DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014377

Submitter: G2P

developmental and epileptic encephalopathy, 24DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014377

Submitter: Ambry Genetics

generalized epilepsy with febrile seizures plus, type 10STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032777

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 24STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014377

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 24; Generalized epilepsy with febrile seizures plus, type 10AD

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: 24747641; 29936235; 30351409Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HCN1 variants in ClinVar

18 Conditions Cataloged
Early-infantile DEETotal: 808
not providedTotal: 329
Inborn genetic diseasesTotal: 149
not specifiedTotal: 72
Developmental and epileptic encephalopathy, 24Total: 57
HCN1-related disorderTotal: 47
Generalized epilepsy with febrile seizures plus, type 10Total: 44
Developmental and epileptic encephalopathyTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021072.4. 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.

EffectPLPVUSLBBSum
synonymous
7
clinvar
288
clinvar
5
clinvar
 300
missense
19
clinvar
28
clinvar
504
clinvar
87
clinvar
1
clinvar
 639
nonsense
17
clinvar
1
clinvar
 18
start loss
3
clinvar
 3
frameshift
2
clinvar
25
clinvar
 27
splice donor/acceptor (+/-2bp)
10
clinvar
 10
Total19305663766997

Highest pathogenic variant AF is 0.000044621775

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_021072.4RefSeqNP_066550.28MANE Select
ENST00000303230.6EnsemblENSP00000307342.48MANE Select
ENST00000634658.1EnsemblENSP00000489134.12Standard
ENST00000673735.1EnsemblENSP00000501107.18Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neuronal System
  • HCN channels
  • Potassium Channels

Biological Process

  • regulation of ion transmembrane transport
  • sodium ion transmembrane transport
  • regulation of membrane potential
  • apical protein localization
  • retinal cone cell development

Molecular Function

  • intracellular cAMP-activated cation channel activity
  • voltage-gated sodium channel activity
  • voltage-gated potassium channel activity
  • potassium channel activity
  • protein binding

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • axon
  • dendrite
  • HCN channel complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000303230
Coding exons
8
Length
436905
Individuals with no LoFs
125743
Homozygous LoFs
0
Heterozygous LoFs
5
Defined
125748
p
0.0000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.662614890.5340.00002785792
Missense (PolyPhen)80216.20.370022516
Synonymous-2.322422001.210.00001301801
Loss of Function5.15234.80.05750.00000196377

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000440.000044rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions (PubMed:28086084). Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). May mediate responses to sour stimuli. {ECO:0000269|PubMed:15351778, ECO:0000269|PubMed:28086084}.;
Disease
DISEASE: Epileptic encephalopathy, early infantile, 24 (EIEE24) [MIM:615871]: A disease characterized by early-onset seizures, intellectual disability of varying degrees, and behavioral disturbances or autistic features in most individuals. {ECO:0000269|PubMed:24747641, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.163

Intolerance Scores

LoFtool
0.111
RVIS EVS
-0.76
RVIS percentile EVS
13.33

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.801

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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