Generalized epilepsy with febrile seizures plus, type 1

Summary

Generalized epilepsy with febrile seizures plus, type 1 (MONDO:0011416) is a disease caused by SCN1B (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: SCN1B (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 113

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	generalized epilepsy with febrile seizures plus, type 1
Mondo ID	MONDO:0011416
MeSH	C565809
OMIM	604233
DOID	DOID:0111302
UMLS	C1858672
MedGen	348994
GARD	0018659
Is cancer (heuristic)	no

Also known as: GEFSP1 · generalized epilepsy with febrile seizures plus, type 1

Data availability: 113 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › hereditary generalized epilepsy › generalized epilepsy with febrile seizures plus › generalized epilepsy with febrile seizures plus, type 1

Related subtypes (9): generalized epilepsy with febrile seizures plus, type 2, febrile seizures, familial, 8, generalized epilepsy with febrile seizures plus, type 4, generalized epilepsy with febrile seizures plus, type 6, generalized epilepsy with febrile seizures plus, type 8, generalized epilepsy with febrile seizures plus, type 7, generalized epilepsy with febrile seizures plus, type 9, generalized epilepsy with febrile seizures plus, type 10, generalized epilepsy with febrile seizures plus, type 12

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

113 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 21 conflicting classifications of pathogenicity, 16 pathogenic, 16 benign/likely benign, 8 benign, 6 pathogenic/likely pathogenic, 4 not provided, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12885	NM_001165963.4(SCN1A):c.4057G>C (p.Val1353Leu)	LOC102724058	Pathogenic	no assertion criteria provided
12886	NM_001165963.4(SCN1A):c.4968C>G (p.Ile1656Met)	LOC102724058	Pathogenic	criteria provided, single submitter
12887	NM_001165963.4(SCN1A):c.3610T>C (p.Trp1204Arg)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
68642	NM_001165963.4(SCN1A):c.4969C>T (p.Arg1657Cys)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
68648	NM_001165963.4(SCN1A):c.5054C>T (p.Ala1685Val)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
68664	NM_001165963.4(SCN1A):c.5555T>C (p.Met1852Thr)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
12883	NM_001165963.4(SCN1A):c.2624C>T (p.Thr875Met)	SCN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12891	NM_001165963.4(SCN1A):c.3809A>C (p.Lys1270Thr)	SCN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
12892	NM_001165963.4(SCN1A):c.4283T>C (p.Val1428Ala)	SCN1A	Pathogenic	no assertion criteria provided
3773645	NM_001165963.4(SCN1A):c.3967C>A (p.Pro1323Thr)	SCN1A	Pathogenic	criteria provided, single submitter
68502	NM_001165963.4(SCN1A):c.1130G>A (p.Arg377Gln)	SCN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68514	NM_001165963.4(SCN1A):c.220T>C (p.Ser74Pro)	SCN1A	Pathogenic	criteria provided, single submitter
68586	NM_001165963.4(SCN1A):c.1162T>C (p.Tyr388His)	SCN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
68590	NM_001165963.4(SCN1A):c.2369A>G (p.Tyr790Cys)	SCN1A	Pathogenic	criteria provided, single submitter
915838	NM_001165963.4(SCN1A):c.2867T>C (p.Met956Thr)	SCN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68592	NM_001165963.4(SCN1A):c.2575C>T (p.Arg859Cys)	SCN1A-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
190859	NM_001037.5(SCN1B):c.253C>T (p.Arg85Cys)	SCN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60767	NM_001037.5(SCN1B):c.254G>A (p.Arg85His)	SCN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694617	NM_001037.5(SCN1B):c.449-2A>G	SCN1B	Pathogenic	reviewed by expert panel
9252	NM_001037.5(SCN1B):c.363C>G (p.Cys121Trp)	SCN1B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9253	NM_001037.5(SCN1B):c.208-2A>C	SCN1B	Pathogenic	no assertion criteria provided
625760	GRCh37/hg19 19q13.11-13.12(chr19:35111811-37744992)	ZFP82	Pathogenic	criteria provided, single submitter
3778727	NM_001165963.4(SCN1A):c.3899C>A (p.Thr1300Lys)	LOC102724058	Likely pathogenic	criteria provided, single submitter
12884	NM_001165963.4(SCN1A):c.563A>T (p.Asp188Val)	SCN1A	Likely pathogenic	criteria provided, single submitter
68625	NM_001165963.4(SCN1A):c.3925C>T (p.Leu1309Phe)	LOC102724058	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68628	NM_001165963.4(SCN1A):c.4096G>A (p.Val1366Ile)	LOC102724058	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68660	NM_001165963.4(SCN1A):c.5383G>A (p.Glu1795Lys)	LOC102724058	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638433	NM_001165963.4(SCN1A):c.2020G>C (p.Asp674His)	SCN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68582	NM_001165963.4(SCN1A):c.80G>C (p.Arg27Thr)	SCN1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190847	NM_001037.5(SCN1B):c.448+193G>A	SCN1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SCN1B	Definitive	Autosomal dominant	generalized epilepsy with febrile seizures plus, type 1	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1B	Orphanet:130	Brugada syndrome
SCN1B	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN1B	Orphanet:33069	Dravet syndrome
SCN1B	Orphanet:334	Hereditary atrial fibrillation
SCN1B	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1B	Orphanet:871	Hereditary progressive cardiac conduction defect
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1B	HGNC:10586	ENSG00000105711	Q07699	Sodium channel regulatory subunit beta-1	gencc,clinvar
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	clinvar
ZFP82	HGNC:28682	ENSG00000181007	Q8N141	Zinc finger protein 82 homolog	clinvar
SCN1A-AS1	HGNC:54069	ENSG00000236107		SCN1A and SCN9A antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1B	Sodium channel regulatory subunit beta-1	Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes.
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
ZFP82	Zinc finger protein 82 homolog	May be involved in transcriptional regulation.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	1	27.9×	0.142
Antibody/Immunoglobulin	1	7.3×	0.260
Transcription factor	1	2.1×	0.538
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1B	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Na_channel_b1/b3
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
ZFP82	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
SCN1A-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primary visual cortex	2
primordial germ cell in gonad	2
cerebellum	1
right hemisphere of cerebellum	1
Brodmann (1909) area 23	1
lateral nuclear group of thalamus	1
cortical plate	1
secondary oocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1B	133	ubiquitous	marker	primary visual cortex, right hemisphere of cerebellum, cerebellum
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
ZFP82	227	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, cortical plate
SCN1A-AS1	129	tissue_specific	marker	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN1A	2,287
SCN1B	1,328
ZFP82	369
SCN1A-AS1	0

Intra-cohort edges

A	B	Sources
SCN1A	SCN1B	biogrid_interaction, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN1B	Q07699	39
SCN1A	P35498	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZFP82	Q8N141	69.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	2	368.4×	4e-05	SCN1B, SCN1A
Phase 0 - rapid depolarisation	2	346.1×	4e-05	SCN1B, SCN1A
L1CAM interactions	2	120.2×	2e-04	SCN1B, SCN1A
Cardiac conduction	2	108.8×	2e-04	SCN1B, SCN1A
Muscle contraction	2	77.2×	4e-04	SCN1B, SCN1A
Axon guidance	2	45.1×	8e-04	SCN1B, SCN1A
Nervous system development	2	42.9×	8e-04	SCN1B, SCN1A
Developmental Biology	2	14.5×	0.007	SCN1B, SCN1A
Sensory perception of taste	1	167.9×	0.007	SCN1B
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	139.3×	0.008	SCN1B
Sensory Perception	1	47.6×	0.021	SCN1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
membrane depolarization during action potential	2	1123.5×	2e-05	SCN1B, SCN1A
neuronal action potential propagation	2	936.2×	2e-05	SCN1B, SCN1A
cardiac muscle cell action potential involved in contraction	2	468.1×	6e-05	SCN1B, SCN1A
sodium ion transmembrane transport	2	135.4×	5e-04	SCN1B, SCN1A
corticospinal neuron axon guidance	1	5617.3×	0.001	SCN1B
membrane depolarization during Purkinje myocyte cell action potential	1	1872.4×	0.002	SCN1B
positive regulation of voltage-gated sodium channel activity	1	1872.4×	0.002	SCN1B
regulation of atrial cardiac muscle cell membrane depolarization	1	624.1×	0.006	SCN1B
cardiac conduction	1	561.7×	0.006	SCN1B
locomotion	1	510.7×	0.006	SCN1B
membrane depolarization during cardiac muscle cell action potential	1	468.1×	0.006	SCN1B
detection of mechanical stimulus involved in sensory perception of pain	1	374.5×	0.006	SCN1A
neuromuscular process controlling posture	1	351.1×	0.006	SCN1A
regulation of sodium ion transmembrane transport	1	351.1×	0.006	SCN1B
nerve development	1	312.1×	0.006	SCN1A
positive regulation of sodium ion transport	1	280.9×	0.006	SCN1B
regulation of ventricular cardiac muscle cell membrane repolarization	1	280.9×	0.006	SCN1B
membrane depolarization	1	170.2×	0.009	SCN1B
adult walking behavior	1	165.2×	0.009	SCN1A
neuronal action potential	1	160.5×	0.009	SCN1A
determination of adult lifespan	1	144.0×	0.010	SCN1A
cardiac muscle contraction	1	133.8×	0.010	SCN1B
regulation of heart rate by cardiac conduction	1	124.8×	0.010	SCN1B
sodium ion transport	1	90.6×	0.013	SCN1A
establishment of localization in cell	1	53.5×	0.022	SCN1A
positive regulation of neuron projection development	1	45.7×	0.024	SCN1B
axon guidance	1	30.2×	0.035	SCN1B
cell adhesion	1	12.5×	0.081	SCN1B
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ZFP82

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SCN1A	MEXILETINE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN1A	94	4
SCN1B	2	2
ZFP82	0	0
SCN1A-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
SCN1B	15	Binding:7, ADMET:6, Toxicity:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SCN1A	149

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN1A
B	Phased (≥1) drug, not yet approved	1	SCN1B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ZFP82, SCN1A-AS1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ZFP82	0	—
SCN1A-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.