SCN3A

Chr 2AD

sodium voltage-gated channel alpha subunit 3

Also known as: DEE62, EIEE62, FFEVF4, NAC3, Nav1.3

NCBI Gene: 6328 ENSG00000153253 UniProt: Q9NY46 OMIM: 182391

Encodes a voltage-gated sodium channel alpha subunit that generates and propagates action potentials in neurons. Mutations cause developmental and epileptic encephalopathy 62 and familial focal epilepsy with variable foci through an autosomal dominant inheritance pattern. The gene is highly intolerant to loss-of-function variants, and mutations can cause disease predominantly through gain-of-function effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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 found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

GOF/LOFmechanismADLOEUF 0.172 OMIM phenotypes

VCEP Guidelines: Epilepsy Sodium ChannelReleased

View Specifications ClinGen Panel

Clinical Summary— SCN3A

🧬

Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

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.

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.17LOEUF

pLI 1.000

Z-score 7.63

OE 0.10 (0.06–0.17)

Highly constrained

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

Missense Constraint?

4.62Z-score

OE missense 0.60 (0.56–0.64)

629 obs / 1050.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.10 (0.06–0.17)

0≤0.351.4

Missense OE?0.60 (0.56–0.64)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 8 / 83.1Missense obs/exp: 629 / 1050.1Syn Z: -1.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSCN3A-related focal epilepsyOTHERAD

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

Nav1.3 sodium channel. GOF variants with increased persistent current cause DEE. LOF variants associated with milder epilepsy phenotypes. Mechanism is variant-specific.1

This gene — mechanism propensity

0.5672th %ile

GOF

0.74top 25%

LOF

0.52top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). 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.

LOF1 literature citation · LOEUF 0.17

GOFprediction above median · 1 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

GOFIn conclusion, we report a cohort of four patients with infantile onset epileptic encephalopathy due toÂ de novoÂ heterozygous gain-of-function missense mutations in the geneÂ SCN3AÂ encoding the type 3 voltage gated sodium channel Nav1.3.2

LOFWe discuss the effects of haploinsufficiency of SCN2A and SCN3A on the genetic basis of neurodevelopmental and neurobehavioral disorders and we propose that this haploinsufficiency may be associated not only with epilepsy, but also with autistic features.3

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

References