SCN1B

Chr 19ADAR

sodium voltage-gated channel beta subunit 1

Also known as: ATFB13, BRGDA5, DEE52, EIEE52, GEFSP1

NCBI Gene: 6324 ENSG00000105711 UniProt: Q07699 OMIM: 600235

The protein encodes the beta-1 subunit of voltage-gated sodium channels, which modulates the kinetics of channel inactivation during action potential generation and propagation in muscle and neuronal cells. Mutations cause generalized epilepsy with febrile seizures plus, developmental and epileptic encephalopathy, Brugada syndrome, and cardiac conduction defects through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves gain-of-function effects on sodium channel activity.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Voltage-gated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells. They are composed of one alpha and two beta subunits, where the alpha subunit provides channel activity and the beta-1 subunit modulates the kinetics of channel inactivation. This gene encodes a sodium channel beta-1 subunit. Mutations in this gene result in generalized epilepsy with febrile seizures plus, Brugada syndrome 5, and defects in cardiac conduction. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 1.265 OMIM phenotypes

VCEP Guidelines: Epilepsy Sodium ChannelReleased

View Specifications ClinGen Panel

Clinical Summary— SCN1B

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Gene-Disease Validity (ClinGen)

generalized epilepsy with febrile seizures plus · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.10) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

37 unique Pathogenic / Likely Pathogenic· 370 VUS of 707 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SCN1B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.26LOEUF

pLI 0.102

Z-score 1.22

OE 0.41 (0.17–1.26)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.22Z-score

OE missense 0.73 (0.63–0.85)

118 obs / 161.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.17–1.26)

0≤0.351.4

Missense OE?0.73 (0.63–0.85)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 2 / 4.9Missense obs/exp: 118 / 161.8Syn Z: -0.06

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSCN1B-related generalized epilepsy with febrile seizures plus or temporal lobe epilepsyOTHERAD

limitedSCN1B-related Brugada syndromeOTHERAD

definitiveSCN1B-related developmental and epileptic encephalopathyOTHERAR

This gene — mechanism propensity

0.6938th %ile

GOF

0.76top 25%

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. 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

GOFOur results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.1

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

References

1.PMID 22155597 ↗

ClinVar Variant Classifications

707 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic10

VUS370

Likely Benign203

Benign35

Conflicting59

Pathogenic

Likely Pathogenic

370

VUS

203

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	4	0	0	27
Likely Pathogenic	5	5	0	0	10
VUS	32	298	31	9	370
Likely Benign	0	11	66	126	203
Benign	0	3	31	1	35
Conflicting	—				59
Total	60	321	128	136	704

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap SCN1B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →