Epilepsy, familial focal, with variable foci 1

Summary

Epilepsy, familial focal, with variable foci 1 (MONDO:0024556) is a disease caused by DEPDC5 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: DEPDC5 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 286

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	epilepsy, familial focal, with variable foci 1
Mondo ID	MONDO:0024556
OMIM	604364
DOID	DOID:0081421
NCIT	C161005
UMLS	C4551983
MedGen	1641798
GARD	0018202
Is cancer (heuristic)	no

Also known as: DEPDC5 epilepsy, familial focal, with variable foci · epilepsy, familial focal, with variable foci 1 · epilepsy, familial focal, with variable foci caused by mutation in DEPDC5 · FFEVF1

Data availability: 286 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › focal epilepsy › familial partial epilepsy › familial focal epilepsy with variable foci › epilepsy, familial focal, with variable foci 1

Related subtypes (3): epilepsy, familial focal, with variable foci 2, epilepsy, familial focal, with variable foci 3, epilepsy, familial focal, with variable foci 4

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

286 retrieved; paginated sample, class counts are floors:

108 uncertain significance, 73 pathogenic, 50 likely pathogenic, 19 conflicting classifications of pathogenicity, 13 not provided, 9 pathogenic/likely pathogenic, 6 benign/likely benign, 4 benign, 3 likely benign, 1 pathogenic, low penetrance

ClinVar	Variant (HGVS)	Gene	Classification	Review
975076	NM_000085.5(CLCNKB):c.226C>T (p.Arg76Ter)	CLCNKB	Pathogenic	criteria provided, multiple submitters, no conflicts
1174127	NM_001242896.3(DEPDC5):c.279+1G>C	DEPDC5	Pathogenic	no assertion criteria provided
1297052	NM_001242896.3(DEPDC5):c.767+1G>A	DEPDC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299564	NM_001242896.3(DEPDC5):c.147-2A>C	DEPDC5	Pathogenic	criteria provided, single submitter
1301854	NM_001242896.3(DEPDC5):c.4673G>A (p.Trp1558Ter)	DEPDC5	Pathogenic	no assertion criteria provided
139433	NM_001242896.3(DEPDC5):c.3259C>T (p.Arg1087Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
139434	NM_001242896.3(DEPDC5):c.1459C>T (p.Arg487Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
1427607	NM_001242896.3(DEPDC5):c.4402C>T (p.Arg1468Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
1701433	NM_001242896.3(DEPDC5):c.625-2A>G	DEPDC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1712487	NM_001242896.3(DEPDC5):c.413+1G>A	DEPDC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803959	NM_001242896.3(DEPDC5):c.546G>A (p.Trp182Ter)	DEPDC5	Pathogenic	criteria provided, single submitter
180644	NM_001242896.3(DEPDC5):c.2527C>T (p.Arg843Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
183029	NM_001242896.3(DEPDC5):c.2355-2A>G	DEPDC5	Pathogenic	criteria provided, single submitter
1878856	NM_001242896.3(DEPDC5):c.1699C>T (p.Arg567Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
190476	NM_001242896.3(DEPDC5):c.418C>T (p.Gln140Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
2067137	NM_001242896.3(DEPDC5):c.1465_1466del (p.His490fs)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
2504650	NM_001242896.3(DEPDC5):c.3564-1G>C	DEPDC5	Pathogenic	criteria provided, single submitter
2580197	NM_001242896.3(DEPDC5):c.856C>T (p.Arg286Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
2580198	NM_001242896.3(DEPDC5):c.451del (p.Val151fs)	DEPDC5	Pathogenic	no assertion criteria provided
264714	NM_001242896.3(DEPDC5):c.193+1G>A	DEPDC5	Pathogenic	criteria provided, single submitter
264715	NM_001242896.3(DEPDC5):c.279+1G>A	DEPDC5	Pathogenic	criteria provided, single submitter
264718	NM_001242896.3(DEPDC5):c.484-1G>A	DEPDC5	Pathogenic	criteria provided, single submitter
264720	NM_001242896.3(DEPDC5):c.526C>T (p.Gln176Ter)	DEPDC5	Pathogenic	criteria provided, single submitter
264721	NM_001242896.3(DEPDC5):c.624+1G>A	DEPDC5	Pathogenic	criteria provided, single submitter
264722	NM_001242896.3(DEPDC5):c.730C>T (p.Gln244Ter)	DEPDC5	Pathogenic	no assertion criteria provided
264723	NM_001242896.3(DEPDC5):c.727C>T (p.Arg243Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
264726	NM_001242896.3(DEPDC5):c.918C>G (p.Tyr306Ter)	DEPDC5	Pathogenic	criteria provided, single submitter
264730	NM_001242896.3(DEPDC5):c.1264C>T (p.Arg422Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
264732	NM_001242896.3(DEPDC5):c.1555C>T (p.Gln519Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts
264734	NM_001242896.3(DEPDC5):c.1759C>T (p.Arg587Ter)	DEPDC5	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 9 · 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
DEPDC5	Definitive	Autosomal dominant	epilepsy, familial focal, with variable foci 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DEPDC5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
DEPDC5	Orphanet:98784	Sleep-related hypermotor epilepsy
DEPDC5	Orphanet:98820	Familial focal epilepsy with variable foci
SCN3A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN3A	Orphanet:98820	Familial focal epilepsy with variable foci
NPRL3	Orphanet:98820	Familial focal epilepsy with variable foci
CLCNKB	Orphanet:358	Gitelman syndrome
CLCNKB	Orphanet:89938	Bartter syndrome type 4
CLCNKB	Orphanet:93605	Bartter syndrome type 3

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DEPDC5	HGNC:18423	ENSG00000100150	O75140	GATOR1 complex protein DEPDC5	gencc,clinvar
SCN3A	HGNC:10590	ENSG00000153253	Q9NY46	Sodium channel protein type 3 subunit alpha	clinvar
NPRL3	HGNC:14124	ENSG00000103148	Q12980	GATOR1 complex protein NPRL3	clinvar
CLCNKB	HGNC:2027	ENSG00000184908	P51801	Chloride channel protein ClC-Kb	clinvar
MPG	HGNC:7211	ENSG00000103152	P29372	DNA-3-methyladenine glycosylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DEPDC5	GATOR1 complex protein DEPDC5	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
SCN3A	Sodium channel protein type 3 subunit alpha	Pore-forming subunit of Nav1.3, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
NPRL3	GATOR1 complex protein NPRL3	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
CLCNKB	Chloride channel protein ClC-Kb	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.
MPG	DNA-3-methyladenine glycosylase	Hydrolysis of the deoxyribose N-glycosidic bond to excise 3-methyladenine, and 7-methylguanine from the damaged DNA polymer formed by alkylation lesions.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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	22.3×	0.132
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DEPDC5	Other/Unknown	no		DEP_dom, IML1, WH-like_DNA-bd_sf
SCN3A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
NPRL3	Other/Unknown	no		Npr3, HTH_NPRL3
CLCNKB	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K
MPG	Enzyme (other)	yes	3.2.2.21	MPG, Formyl_transferase-like_C_sf, MPG_sf

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
frontal pole	1
middle frontal gyrus	1
paraflocculus	1
cortical plate	1
endothelial cell	1
middle temporal gyrus	1
blood	1
hindlimb stylopod muscle	1
right uterine tube	1
adult mammalian kidney	1
metanephros cortex	1
renal medulla	1
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DEPDC5	236	ubiquitous	marker	paraflocculus, frontal pole, middle frontal gyrus
SCN3A	221	broad	marker	endothelial cell, cortical plate, middle temporal gyrus
NPRL3	276	ubiquitous	marker	blood, hindlimb stylopod muscle, right uterine tube
CLCNKB	165	broad	marker	renal medulla, adult mammalian kidney, metanephros cortex
MPG	280	ubiquitous	marker	ascending aorta, thoracic aorta, descending thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPRL3	1,511
SCN3A	1,454
DEPDC5	1,273
MPG	983
CLCNKB	767

Intra-cohort edges

A	B	Sources
DEPDC5	NPRL3	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DEPDC5	O75140	11
NPRL3	Q12980	10
MPG	P29372	9
SCN3A	Q9NY46	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLCNKB	P51801	87.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Amino acids regulate mTORC1	2	80.1×	0.005	DEPDC5, NPRL3
Depurination	1	326.3×	0.024	MPG
Resolution of Abasic Sites (AP sites)	1	228.4×	0.024	MPG
Displacement of DNA glycosylase by APEX1	1	207.6×	0.024	MPG
Base-Excision Repair, AP Site Formation	1	175.7×	0.024	MPG
Base Excision Repair	1	142.8×	0.024	MPG
Interaction between L1 and Ankyrins	1	73.7×	0.035	SCN3A
Phase 0 - rapid depolarisation	1	69.2×	0.035	SCN3A
Sensory perception of taste	1	67.2×	0.035	SCN3A
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	55.7×	0.037	SCN3A
Recognition and association of DNA glycosylase with site containing an affected purine	1	40.8×	0.042	MPG
Cleavage of the damaged purine	1	40.8×	0.042	MPG
Stimuli-sensing channels	1	27.2×	0.059	CLCNKB
L1CAM interactions	1	24.0×	0.061	SCN3A
Cardiac conduction	1	21.8×	0.063	SCN3A
DNA Repair	1	19.7×	0.064	MPG
Sensory Perception	1	19.0×	0.064	SCN3A
Muscle contraction	1	15.4×	0.074	SCN3A
Axon guidance	1	9.0×	0.117	SCN3A
Nervous system development	1	8.6×	0.117	SCN3A
Developmental Biology	1	2.9×	0.301	SCN3A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of TORC1 signaling	2	129.6×	1e-03	DEPDC5, NPRL3
cellular response to amino acid starvation	2	127.2×	1e-03	DEPDC5, NPRL3
positive regulation of autophagy	2	83.2×	0.002	DEPDC5, NPRL3
depurination	1	842.6×	0.006	MPG
transepithelial chloride transport	1	374.5×	0.008	CLCNKB
renal absorption	1	337.0×	0.008	CLCNKB
membrane depolarization during action potential	1	337.0×	0.008	SCN3A
DNA alkylation repair	1	306.4×	0.008	MPG
renal sodium ion absorption	1	198.3×	0.009	CLCNKB
aorta morphogenesis	1	177.4×	0.009	NPRL3
behavioral response to pain	1	177.4×	0.009	SCN3A
cardiac muscle tissue development	1	177.4×	0.009	NPRL3
cardiac muscle cell action potential involved in contraction	1	140.4×	0.011	SCN3A
ventricular septum development	1	99.1×	0.014	NPRL3
base-excision repair	1	93.6×	0.014	MPG
chloride transport	1	91.1×	0.014	CLCNKB
sodium ion transport	1	54.4×	0.021	SCN3A
roof of mouth development	1	49.6×	0.022	NPRL3
sodium ion transmembrane transport	1	40.6×	0.026	SCN3A
intracellular signal transduction	1	7.6×	0.124	DEPDC5

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
SCN3A	BEPRIDIL
MPG	MITOXANTRONE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN3A	93	4
MPG	2	4
DEPDC5	0	0
NPRL3	0	0
CLCNKB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN3A
DIBUCAINE	4	SCN3A
ARTICAINE	4	SCN3A
BUPIVACAINE	4	SCN3A
IMIPRAMINE	4	SCN3A
DROPERIDOL	4	SCN3A
DICYCLOMINE	4	SCN3A
TETRABENAZINE	4	SCN3A
PHENIRAMINE	4	SCN3A
PRILOCAINE	4	SCN3A
PROPOXYCAINE	4	SCN3A
PROPARACAINE	4	SCN3A
HEXYLCAINE	4	SCN3A
PRAMOXINE	4	SCN3A
BENOXINATE	4	SCN3A
QUINIDINE	4	SCN3A
FELODIPINE	4	SCN3A
PHENYTOIN	4	SCN3A
QUININE	4	SCN3A
NISOLDIPINE	4	SCN3A
NIFEDIPINE	4	SCN3A
PRAZOSIN	4	SCN3A
DILTIAZEM	4	SCN3A
PRENYLAMINE	4	SCN3A
COCAINE	4	SCN3A
TRIFLUOPERAZINE	4	SCN3A
CINNARIZINE	4	SCN3A
THIORIDAZINE	4	SCN3A
ETIDOCAINE	4	SCN3A
CHLORPHENIRAMINE	4	SCN3A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SCN3A	102	Binding:79, Functional:18, ADMET:4, Toxicity:1
MPG	12	Binding:11, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MPG	3.2.2.21	DNA-3-methyladenine glycosylase II

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN3A	102

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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)
BEPRIDIL	4	SCN3A
DIBUCAINE	4	SCN3A
ARTICAINE	4	SCN3A
BUPIVACAINE	4	SCN3A
IMIPRAMINE	4	SCN3A
DROPERIDOL	4	SCN3A
DICYCLOMINE	4	SCN3A
TETRABENAZINE	4	SCN3A
PHENIRAMINE	4	SCN3A
PRILOCAINE	4	SCN3A
PROPOXYCAINE	4	SCN3A
PROPARACAINE	4	SCN3A
HEXYLCAINE	4	SCN3A
PRAMOXINE	4	SCN3A
BENOXINATE	4	SCN3A
QUINIDINE	4	SCN3A
FELODIPINE	4	SCN3A
PHENYTOIN	4	SCN3A
QUININE	4	SCN3A
NISOLDIPINE	4	SCN3A
NIFEDIPINE	4	SCN3A
PRAZOSIN	4	SCN3A
DILTIAZEM	4	SCN3A
PRENYLAMINE	4	SCN3A
COCAINE	4	SCN3A
TRIFLUOPERAZINE	4	SCN3A
CINNARIZINE	4	SCN3A
THIORIDAZINE	4	SCN3A
ETIDOCAINE	4	SCN3A
CHLORPHENIRAMINE	4	SCN3A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCN3A, MPG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	DEPDC5, NPRL3, CLCNKB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DEPDC5	0	—
NPRL3	0	—
CLCNKB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.