HCN1

Chr 5AD

hyperpolarization activated cyclic nucleotide gated potassium channel 1

Also known as: BCNG-1, BCNG1, DEE24, EIEE24, GEFSP10, HAC-2

NCBI Gene: 348980 ENSG00000164588 UniProt: O60741 OMIM: 602780

This gene encodes a hyperpolarization-activated cation channel that contributes to pacemaker currents in neurons and can form homo- or heterodimeric potassium channels. Mutations cause developmental and epileptic encephalopathy 24 and generalized epilepsy with febrile seizures plus type 10 through an autosomal dominant inheritance pattern. The pathogenic mechanism appears to predominantly involve loss-of-function, consistent with the gene's high intolerance to loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.182 OMIM phenotypes

Clinical Summary— HCN1

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Gene-Disease Validity (ClinGen)

generalized epilepsy with febrile seizures plus · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 5.15

OE 0.06 (0.02–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.66Z-score

OE missense 0.53 (0.48–0.59)

261 obs / 489.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.18)

0≤0.351.4

Missense OE?0.53 (0.48–0.59)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 2 / 34.8Missense obs/exp: 261 / 489.1Syn Z: -2.32

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHCN1-related epileptic encephalopathy, early infantileOTHERAD

Mechanism Note (expert annotation)

GOF

HCN1 forms tetrameric channels. DEE variants show GOF with enhanced Ih current and depolarized activation. G2P classifies as undetermined but electrophysiology data supports GOF.1

This gene — mechanism propensity

0.5378th %ile

GOF

0.7126th %ile

LOF

0.67top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.18

GOFprediction above median · 1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNStrikingly, Arg297Thr and, to a lesser extent, Ser100Phe and Ser272Pro HCN1 but not Asp401His had a dominant-negative effect on the wild-type form, decreasing the current density of heteromeric channels.2

GOFElectrophysiologic patch-clamp studies in CHO cells showed divergent effects of the mutations. Some had a major effect on channel gating, resulting in a gain of function, whereas no current was recorded for others. Most, but not all, showed a dominant-negative effect.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References