SCN1A

Chr 2AD

sodium voltage-gated channel alpha subunit 1

Also known as: DEE6, DEE6A, DEE6B, DRVT, EIEE6, FEB3, FEB3A, FHM3

NCBI Gene: 6323 ENSG00000144285 UniProt: P35498

Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 6B, non-DravetMIM #619317

Dravet syndromeMIM #607208

Febrile seizures, familial, 3AMIM #604403

Generalized epilepsy with febrile seizures plus, type 2MIM #604403

Migraine, familial hemiplegic, 3MIM #609634

UniProtIntractable childhood epilepsy with generalized tonic-clonic seizures

600

ClinVar variants

199

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— SCN1A

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Gene-Disease Validity (ClinGen)

generalized epilepsy with febrile seizures plus · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

4 total gene-disease associations curated

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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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ClinVar Variants

199 Pathogenic / Likely Pathogenic· 278 VUS of 600 total submissions

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Clinical Trials

8 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.07LOEUF

pLI 1.000

Z-score 8.52

OE 0.02 (0.01–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

5.22Z-score

OE missense 0.55 (0.51–0.59)

590 obs / 1070.7 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.02 (0.01–0.07)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.51–0.59)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94

0≤1.21.6

LoF obs/exp: 2 / 88.5Missense obs/exp: 590 / 1070.7Syn Z: 0.88

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic105

Likely Pathogenic94

VUS278

Likely Benign110

Benign8

Conflicting5

105

Pathogenic

Likely Pathogenic

278

VUS

110

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	34	32	39	0	105
Likely Pathogenic	21	65	8	0	94
VUS	3	232	39	4	278
Likely Benign	0	2	41	67	110
Benign	0	0	6	2	8
Conflicting	—				5
Total	58	331	133	73	600

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

View in ClinVar →

Protein Context — Lollipop Plot

SCN1A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SCN1A-related seizure disorders

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 1; SCN1A

MIM #182389 · *

Developmental and epileptic encephalopathy 6B, non-Dravet

MIM #619317