Familial temporal lobe epilepsy 7

Summary

Familial temporal lobe epilepsy 7 (MONDO:0014639) is a disease caused by RELN (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: RELN (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 3,346

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial temporal lobe epilepsy 7
Mondo ID	MONDO:0014639
OMIM	616436
DOID	DOID:0060751
UMLS	C4225327
MedGen	907609
GARD	0016112
Is cancer (heuristic)	no

Also known as: epilepsy, familial temporal lobe, 7 · epilepsy, familial temporal lobe, type 7 · ETL7 · familial temporal lobe epilepsy type 7

Data availability: 3,346 ClinVar variants · 3 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 › temporal lobe epilepsy › familial temporal lobe epilepsy 7

Related subtypes (5): familial temporal lobe epilepsy 2, familial temporal lobe epilepsy 4, familial temporal lobe epilepsy 8, epilepsy, familial temporal lobe, 1, familial mesial temporal lobe epilepsy

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

600 retrieved; paginated sample, class counts are floors:

282 uncertain significance, 233 likely benign, 41 conflicting classifications of pathogenicity, 19 benign, 13 benign/likely benign, 8 pathogenic, 3 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074036	NM_005045.4(RELN):c.3871C>T (p.Arg1291Ter)	RELN	Pathogenic	criteria provided, single submitter
1074751	NM_005045.4(RELN):c.4190del (p.Asn1397fs)	RELN	Pathogenic	criteria provided, single submitter
1325004	NM_005045.4(RELN):c.4864C>T (p.Arg1622Ter)	RELN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1355125	NM_005045.4(RELN):c.4639C>T (p.Arg1547Ter)	RELN	Pathogenic	criteria provided, single submitter
1363442	NM_005045.4(RELN):c.8047G>T (p.Glu2683Ter)	RELN	Pathogenic	criteria provided, single submitter
1371832	NM_005045.4(RELN):c.4510A>T (p.Arg1504Ter)	RELN	Pathogenic	criteria provided, single submitter
1377194	NM_005045.4(RELN):c.3378G>A (p.Trp1126Ter)	RELN	Pathogenic	criteria provided, single submitter
1388018	NM_005045.4(RELN):c.4904_4905insA (p.Met1635fs)	RELN	Pathogenic	criteria provided, single submitter
1397755	NM_005045.4(RELN):c.6474del (p.Cys2159fs)	RELN	Pathogenic	criteria provided, single submitter
1066513	NM_005045.4(RELN):c.2303+1G>A	RELN	Likely pathogenic	criteria provided, single submitter
1066813	NM_005045.4(RELN):c.5615-2A>G	RELN	Likely pathogenic	criteria provided, single submitter
1186074	NM_005045.4(RELN):c.3912+2T>G	RELN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1397456	NM_005045.4(RELN):c.9447G>A (p.Ser3149=)	LOC126860130	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001773	NM_005045.4(RELN):c.9589G>A (p.Asp3197Asn)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002525	NM_005045.4(RELN):c.5360G>A (p.Arg1787Gln)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003493	NM_005045.4(RELN):c.65G>A (p.Arg22Lys)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006697	NM_005045.4(RELN):c.6079G>A (p.Val2027Ile)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023132	NM_005045.4(RELN):c.10267G>A (p.Val3423Met)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025631	NM_005045.4(RELN):c.5398C>G (p.Leu1800Val)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032971	NM_005045.4(RELN):c.4918A>G (p.Ile1640Val)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1040114	NM_005045.4(RELN):c.4403C>G (p.Ala1468Gly)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1040242	NM_005045.4(RELN):c.5246A>G (p.Asn1749Ser)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042288	NM_005045.4(RELN):c.718G>A (p.Val240Ile)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043796	NM_005045.4(RELN):c.1915C>A (p.Leu639Ile)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1053644	NM_005045.4(RELN):c.589A>G (p.Ser197Gly)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054171	NM_005045.4(RELN):c.5023C>G (p.Pro1675Ala)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1054930	NM_005045.4(RELN):c.1669T>G (p.Phe557Val)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1108525	NM_005045.4(RELN):c.6189C>T (p.Ser2063=)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1285576	NM_005045.4(RELN):c.9281A>G (p.Tyr3094Cys)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130109	NM_005045.4(RELN):c.-24GGC[10] (p.Met1_Glu2insGlyGly)	RELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
RELN	Strong	Autosomal dominant	familial temporal lobe epilepsy 7	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RELN	Orphanet:101046	Epilepsy with auditory features
RELN	Orphanet:89844	Lissencephaly syndrome, Norman-Roberts type
PMPCB	Orphanet:569290	Multiple mitochondrial dysfunctions syndrome type 6

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
RELN	HGNC:9957	ENSG00000189056	P78509	Reelin	gencc,clinvar
SLC26A5-AS1	HGNC:55680	ENSG00000234715		SLC26A5 antisense RNA 1	clinvar
PMPCB	HGNC:9119	ENSG00000105819	O75439	Mitochondrial-processing peptidase subunit beta	clinvar
PSMC2	HGNC:9548	ENSG00000161057	P35998	26S proteasome regulatory subunit 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RELN	Reelin	Extracellular matrix serine protease secreted by pioneer neurons that plays a role in layering of neurons in the cerebral cortex and cerebellum by coordinating cell positioning during neurodevelopment.
PMPCB	Mitochondrial-processing peptidase subunit beta	Catalytic subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.
PSMC2	26S proteasome regulatory subunit 7	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Protease	1	9.2×	0.210
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RELN	Other/Unknown	no		EGF, Reeler_dom, EGF_extracell
SLC26A5-AS1	Other/Unknown	no
PMPCB	Protease	yes	3.4.24.64	Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16
PSMC2	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS

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
cerebellar vermis	1
cerebellum	1
olfactory bulb	1
colonic epithelium	1
oocyte	1
secondary oocyte	1
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
biceps brachii	1
esophagus squamous epithelium	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RELN	254	broad	marker	olfactory bulb, cerebellar vermis, cerebellum
SLC26A5-AS1	111		yes	colonic epithelium, secondary oocyte, oocyte
PMPCB	297	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, adrenal tissue
PSMC2	302	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, esophagus squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSMC2	4,986
PMPCB	4,266
RELN	2,305
SLC26A5-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMC2	P35998	131
RELN	P78509	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PMPCB	O75439	87.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 74. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Reelin signalling pathway	1	634.4×	0.026	RELN
Processing of SMDT1	1	211.5×	0.026	PMPCB
Mitochondrial calcium ion transport	1	181.3×	0.026	PMPCB
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	92.8×	0.026	PSMC2
Regulation of ornithine decarboxylase (ODC)	1	90.6×	0.026	PSMC2
Vpu mediated degradation of CD4	1	88.5×	0.026	PSMC2
Autodegradation of the E3 ubiquitin ligase COP1	1	88.5×	0.026	PSMC2
Ubiquitin-dependent degradation of Cyclin D	1	88.5×	0.026	PSMC2
Cross-presentation of soluble exogenous antigens (endosomes)	1	84.6×	0.026	PSMC2
Vif-mediated degradation of APOBEC3G	1	84.6×	0.026	PSMC2
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	82.8×	0.026	PSMC2
Degradation of AXIN	1	82.8×	0.026	PSMC2
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	1	82.8×	0.026	PSMC2
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	1	82.8×	0.026	PSMC2
Hh mutants are degraded by ERAD	1	81.0×	0.026	PSMC2
SCF-beta-TrCP mediated degradation of Emi1	1	79.3×	0.026	PSMC2
Degradation of DVL	1	79.3×	0.026	PSMC2
Negative regulation of NOTCH4 signaling	1	79.3×	0.026	PSMC2
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	1	79.3×	0.026	PSMC2
Regulation of RUNX3 expression and activity	1	77.7×	0.026	PSMC2
Somitogenesis	1	77.7×	0.026	PSMC2
NIK–>noncanonical NF-kB signaling	1	76.1×	0.026	PSMC2
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	76.1×	0.026	PSMC2
Degradation of GLI1 by the proteasome	1	74.6×	0.026	PSMC2
Degradation of GLI2 by the proteasome	1	74.6×	0.026	PSMC2
GLI3 is processed to GLI3R by the proteasome	1	74.6×	0.026	PSMC2
Defective CFTR causes cystic fibrosis	1	73.2×	0.026	PSMC2
Degradation of CRY and PER proteins	1	73.2×	0.026	PSMC2
Dectin-1 mediated noncanonical NF-kB signaling	1	71.8×	0.026	PSMC2
Hedgehog ligand biogenesis	1	70.5×	0.026	PSMC2

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
spinal cord patterning	1	5617.3×	0.005	RELN
positive regulation of lateral motor column neuron migration	1	5617.3×	0.005	RELN
lateral motor column neuron migration	1	1872.4×	0.006	RELN
cerebral cortex tangential migration	1	1404.3×	0.006	RELN
regulation of synaptic activity	1	1404.3×	0.006	RELN
NMDA glutamate receptor clustering	1	1123.5×	0.006	RELN
postsynaptic density protein 95 clustering	1	936.2×	0.006	RELN
obsolete protein processing involved in protein targeting to mitochondrion	1	702.2×	0.006	PMPCB
positive regulation of small GTPase mediated signal transduction	1	702.2×	0.006	RELN
receptor localization to synapse	1	702.2×	0.006	RELN
ventral spinal cord development	1	624.1×	0.006	RELN
positive regulation of synapse maturation	1	624.1×	0.006	RELN
postsynaptic density assembly	1	624.1×	0.006	RELN
radial glial cell differentiation	1	510.7×	0.007	RELN
interneuron migration	1	510.7×	0.007	RELN
regulation of behavior	1	468.1×	0.007	RELN
reelin-mediated signaling pathway	1	401.2×	0.007	RELN
layer formation in cerebral cortex	1	374.5×	0.007	RELN
mitochondrial calcium ion transmembrane transport	1	330.4×	0.007	PMPCB
positive regulation of proteasomal protein catabolic process	1	330.4×	0.007	PSMC2
glial cell differentiation	1	295.6×	0.007	RELN
response to pain	1	295.6×	0.007	RELN
positive regulation of dendritic spine morphogenesis	1	295.6×	0.007	RELN
protein localization to synapse	1	255.3×	0.008	RELN
regulation of neuron differentiation	1	244.2×	0.008	RELN
positive regulation of long-term synaptic potentiation	1	224.7×	0.009	RELN
positive regulation of synaptic transmission, glutamatergic	1	208.1×	0.009	RELN
regulation of neuron migration	1	208.1×	0.009	RELN
positive regulation of excitatory postsynaptic potential	1	175.5×	0.010	RELN
positive regulation of TOR signaling	1	165.2×	0.010	RELN

Therapeutics

Drug target analysis

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

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
PSMC2	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMC2	2	4
RELN	0	0
SLC26A5-AS1	0	0
PMPCB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	PSMC2
CARFILZOMIB	4	PSMC2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PSMC2	27	Binding:27
PMPCB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PMPCB	3.4.24.64	mitochondrial processing peptidase

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

2 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)
BORTEZOMIB	4	PSMC2
CARFILZOMIB	4	PSMC2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSMC2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PMPCB
E	Difficult family or no structure, no drug	2	RELN, SLC26A5-AS1

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)
RELN	0	—
SLC26A5-AS1	0	—
PMPCB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.