SCN11A

Chr 3AD

sodium voltage-gated channel alpha subunit 11

Also known as: FEPS3, HSAN7, NAV1.9, NaN, PN5, SCN12A, SNS-2

NCBI Gene: 11280 ENSG00000168356 UniProt: Q9UI33 OMIM: 604385

The protein forms voltage-gated sodium channels that mediate sodium ion permeability in excitable membranes and is highly expressed in nociceptive neurons where it transmits pain signals from the periphery to the central nervous system. Mutations cause familial episodic pain syndrome-3 and hereditary sensory and autonomic neuropathy type VII with autosomal dominant inheritance. The gene shows minimal constraint against loss-of-function variants (very low pLI score), suggesting the associated phenotypes may involve other mutational mechanisms.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is highly expressed in nociceptive neurons of dorsal root ganglia and trigeminal ganglia. It mediates brain-derived neurotrophic factor-evoked membrane depolarization and is a major effector of peripheral inflammatory pain hypersensitivity. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy type VII and familial episodic pain syndrome-3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2017]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.832 OMIM phenotypes

Clinical Summary— SCN11A

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Gene-Disease Validity (ClinGen)

obsolete autosomal dominant hereditary sensory and autonomic neuropathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.000

Z-score 2.84

OE 0.66 (0.53–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.96Z-score

OE missense 0.91 (0.86–0.96)

881 obs / 965.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.66 (0.53–0.83)

0≤0.351.4

Missense OE?0.91 (0.86–0.96)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 53 / 80.5Missense obs/exp: 881 / 965.3Syn Z: -0.25

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSCN11A-related episodic pain syndrome, familialGOFAD

definitiveSCN11A-related congenital inability to experience painGOFAD

This gene — mechanism propensity

0.83top 10%

GOF

0.79top 25%

LOF

0.1796th %ile

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

GOFprediction above median · 1 literature citation

DNprediction above median

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

GOFIn 2013, discovery of a heterozygous gain-of-function mutation in SCN11A encoding voltage-gated sodium channel 1.9 (Nav1.9) established a distinctive CIP in three unrelated patients who suffered multiple painless fractures, self-inflicted mutilation, chronic diarrhea, and hyperhidrosis.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References