LGI1

Summary

LGI1 (leucine rich glioma inactivated 1, HGNC:6572) is a protein-coding gene on chromosome 10q23.33, encoding Leucine-rich glioma-inactivated protein 1 (O95970). Regulates voltage-gated potassium channels assembled from KCNA1, KCNA4 and KCNAB1. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the secreted leucine-rich repeat (LRR) superfamily and shares homology with members of the SLIT protein family. The encoded protein may regulate the activity of voltage-gated potassium channels and may be involved in neuronal growth regulation and cell survival. This gene is rearranged as a result of translocations in glioblastoma cell lines, and it is frequently down-regulated or rearranged in malignant gliomas. Mutations in this gene result in autosomal dominant lateral temporal epilepsy. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 9211 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant epilepsy with auditory features (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 573 total — 44 pathogenic, 28 likely-pathogenic
• Phenotypes (HPO): 100
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005097

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6572
Approved symbol	LGI1
Name	leucine rich glioma inactivated 1
Location	10q23.33
Locus type	gene with protein product
Status	Approved
Aliases	IB1099, ETL1, EPITEMPIN
Ensembl gene	ENSG00000108231
Ensembl biotype	protein_coding
OMIM	604619
Entrez	9211

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 10 nonsense_mediated_decay, 9 protein_coding, 8 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000371413, ENST00000371418, ENST00000464250, ENST00000478763, ENST00000485458, ENST00000626307, ENST00000626946, ENST00000627420, ENST00000627699, ENST00000629035, ENST00000630047, ENST00000630184, ENST00000630412, ENST00000630487, ENST00000635725, ENST00000635804, ENST00000635953, ENST00000636140, ENST00000636155, ENST00000636232, ENST00000636683, ENST00000636754, ENST00000636775, ENST00000636946, ENST00000637037, ENST00000637347, ENST00000637611, ENST00000637689, ENST00000637925, ENST00000638049, ENST00000676175

RefSeq mRNA: 3 — MANE Select: NM_005097 NM_001308275, NM_001308276, NM_005097

CCDS: CCDS7431, CCDS76325, CCDS81490

Canonical transcript exons

ENST00000371418 — 8 exons

Exon	Start	End
ENSE00000715224	93790099	93790170
ENSE00000715228	93777546	93777617
ENSE00000715233	93777379	93777450
ENSE00000986650	93758760	93758831
ENSE00000986651	93792743	93792912
ENSE00000986652	93793186	93793350
ENSE00001455190	93796968	93798159
ENSE00003775383	93757936	93758359

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 97.06.

FANTOM5 (CAGE): breadth broad, TPM avg 7.8039 / max 260.2594, expressed in 397 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106294	4.7789	344
106295	0.7979	216
106292	0.7902	218
106293	0.6131	207
106291	0.5791	210
205950	0.2005	123
205949	0.0443	20

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	97.06	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.69	gold quality
endothelial cell	CL:0000115	96.65	gold quality
caudate nucleus	UBERON:0001873	96.13	gold quality
putamen	UBERON:0001874	95.94	gold quality
middle temporal gyrus	UBERON:0002771	95.78	gold quality
choroid plexus epithelium	UBERON:0003911	95.72	gold quality
nucleus accumbens	UBERON:0001882	95.68	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.31	gold quality
superior frontal gyrus	UBERON:0002661	94.37	gold quality
primary visual cortex	UBERON:0002436	94.30	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.29	gold quality
entorhinal cortex	UBERON:0002728	94.26	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.22	gold quality
postcentral gyrus	UBERON:0002581	93.90	gold quality
Ammon’s horn	UBERON:0001954	93.88	gold quality
cingulate cortex	UBERON:0003027	93.63	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.63	gold quality
cerebellar hemisphere	UBERON:0002245	93.59	gold quality
anterior cingulate cortex	UBERON:0009835	93.56	gold quality
cerebellar cortex	UBERON:0002129	93.55	gold quality
prefrontal cortex	UBERON:0000451	93.28	gold quality
temporal lobe	UBERON:0001871	93.26	gold quality
telencephalon	UBERON:0001893	93.23	gold quality
amygdala	UBERON:0001876	93.17	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.15	gold quality
right frontal lobe	UBERON:0002810	93.07	gold quality
parietal lobe	UBERON:0001872	93.04	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.99	gold quality
cerebellum	UBERON:0002037	92.97	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	11.54
E-ANND-3	yes	5.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ARX, EBF3, ETS2

miRNA regulators (miRDB)

60 targeting LGI1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-488-3P	99.61	68.79	1731

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• mutations cause autosomal-dominant partial epilepsy with auditory features (PMID:11810107)
• Mutations in LGI1 causes autosomal dominant lateral temporal epilepsy (PMID:11978770)
• Shares a homology domain with MASS1, a mouse epilepsy protein (PMID:12095917)
• LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures (PMID:12205652)
• The LGI1 protein has a seven copy-tandem repeat, the EPTP repeat, in its C-terminus. The EPTP repeat is the unifying sequence motif for a heterogenous superfamily of genes associated with epilepsy and other neurological disorders. (PMID:12217514)
• A novel mutation in the Lgi1 signal peptide is predicted to interfere with protein cell sorting, resulting in altered processing. (PMID:12601709)
• A novel F318C substitution alters a highly conserved residue in a predicted repeat domain of LGI1 which may participate in the development of the “autosomal dominant partial epilepsy with auditory features” phenotype. (PMID:12771268)
• LGI1 has a role in cell growth and neoplasm invasiveness in glioma cells (PMID:12821932)
• novel mutations in LGI1 gene are traced to temporal epilepsy. (PMID:15009222)
• Loss of LGI1 expression may be an important event in the progression of gliomas that leads to a more invasive phenotype in these cells (PMID:15047712)
• In temporal lobe epilepsy, mutations in LGI1 are specific for autosomal dominant partial epilepsy with auditory features {ADPEAF} but do not occur in all families; ADPEAF is genetically heterogeneous (PMID:15079010)
• LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features[ADPEAF]. Current data do not reveal a clinical feature clearly predictive of which ADPEAF families have a mutation (PMID:15079011)
• that the evidence supporting the tumor suppressor role of LGI1 in malignant gliomas is weak and that further work is necessary to establish LGI1 role in glial cells (PMID:15827762)
• No analyzed polymorphisms modified susceptibility in either the familial or sporadic forms of this partial epilepsy. (PMID:16707245)
• Two protein isoforms encoded by LGI1/epitempin are differentially expressed in human brain; higher expression levels in lateral temporal cortex may underlie the susceptibility of this brain region to epileptogenic effects of LGI1/epitempin mutations. (PMID:16787412)
• LGI1 is a secreted protein and suggest that LGI1-related epilepsy results from a loss of function. (PMID:17296837)
• We found a structural anomaly of the left lateral temporal lobe in epilepsy due to mutated LGI1. (PMID:17875918)
• no mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene linked to familial or sporadic lateral temporal epilepsy were found (PMID:18355961)
• A novel loss-of-function mutation in LGI1 provides further evidence that mutations in LGI1 hamper secretion of the Lgi1 protein, thereby precluding its normal function. (PMID:18625862)
• About two-thirds of individuals who inherit a mutation in LGI1 will develop epilepsy. This probably overestimates the true penetrance in the population because it is based on data from families containing multiple affected individuals. (PMID:18711109)
• Both truncating and missense mutations appear to prevent secretion of mutant proteins, suggesting a loss of function effect of mutations. (PMID:19191227)
• In a family in which three patients also experienced migraine-like episodes we found a novel three base-pair deletion (c.377_379delACA), resulting in the deletion of an asparagine residue in the second leucine-rich repeat. (PMID:19268539)
• These observations support a role for LGI1 in synapse vesicle function in neurons. (PMID:19387870)
• study describes a family with autosomal dominant lateral temporal epilepsy with a novel mutation in LGI1; proband presented uncommon electroclinical findings like drug-resistant seizures & recurrent episodes of status epilepticus with dysphasic features (PMID:19552651)
• LGI1 may be an important molecule for the arrest of prostate cancer cell invasion and possibly a biomarker for early detection of prostate hyperplasia. (PMID:19778537)
• These findings suggest that LGI1 mutations in Japanese ADLTE families may not be uncommon, and that diverse clinical phenotypes make adequate diagnosis of ADLTE difficult when only based on clinical information. (PMID:19780791)
• Data suggest that LGI1 binding to ADAM23 is necessary to correctly pattern neuronal morphology, and altered anatomical patterning contributes to autosomal dominant partial epilepsy with auditory features. (PMID:19796686)
• The target antigen of antibodies in patients with limbic encephalitis previously attributed to voltage-gated potassium channels is in fact LGI1, a secreted neuronal protein that functions as a ligand for two epilepsy-related proteins, ADAM22 and ADAM23. (PMID:20580615)
• The LGI family members is responsible for phenotypically similar, mechanistically related but genotypically distinct forms of epilepsy. (PMID:20863412)
• Data report a family with temporal lobe epilepsy characterized by psychic symptoms associated with a novel LGI1 mutation. (PMID:21444903)
• A possible arrangement between the two domains and identifies a possible ADAM protein binding site in the beta-propeller domain and another protein binding site in the leucine-rich repeat domain, is suggested. (PMID:21479274)
• mutations in autosomal dominant lateral temporal epilepsy with low penetrance and effects on protein secretion (PMID:21504429)
• LGI1, a secreted synaptic protein mutated to cause human partial epilepsy, regulates a seizure-induced circuit response by redistributing Kv4.2 channels to the neuronal surface in a transgenic mouse model. (PMID:22122031)
• The N-terminal leucine-rich repeat region of the LGI1 gene is likely to play a major role in pathogenesis of autosomal dominant partial epilepsy with auditory features. (PMID:22323750)
• This is the first microdeletion affecting LGI1 identified in autosomal dominant lateral temporal epilepsy. (PMID:22496201)
• Antibodies bind to proteins complexed with voltage-gated potassium channel (VGKC) complex in two patients with LG11-antibody encephalitis. (PMID:22744657)
• Cerebrocortical manifestations are recorded in 76% of patients with LGI1 immunoglobulin G (IgG) seropositivity. (PMID:23407760)
• This study demonistrated that Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations. (PMID:23621105)
• This study expands the phenotypic spectrum associated with Autosomal dominant lateral temporal lobe epilepsy due to LGI1 mutation and underlines the need for more systematic evaluation of Attention-deficit hyperactivity disorder and related symptoms. (PMID:23651915)
• A new LGI1 missense mutation is identified in a large Korean family with autosomal dominant lateral temporal lobe epilepsy. (PMID:24177143)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	lgi1a	ENSDARG00000020493
danio_rerio	lgi1b	ENSDARG00000058421
danio_rerio	si:ch211-191d15.2	ENSDARG00000092834
mus_musculus	Lgi1	ENSMUSG00000067242
rattus_norvegicus	Lgi1	ENSRNOG00000014758
drosophila_melanogaster	Con	FBGN0005775
drosophila_melanogaster	kek3	FBGN0028370
drosophila_melanogaster	CG18095	FBGN0028872
drosophila_melanogaster	CG7509	FBGN0035575
caenorhabditis_elegans	lron-9	WBGENE00011971
caenorhabditis_elegans		WBGENE00020649
caenorhabditis_elegans		WBGENE00022789

Paralogs (22): CHADL (ENSG00000100399), LGR6 (ENSG00000133067), CHAD (ENSG00000136457), LRIG3 (ENSG00000139263), LGR5 (ENSG00000139292), LRIG1 (ENSG00000144749), LRRTM2 (ENSG00000146006), LRIT1 (ENSG00000148602), LGI2 (ENSG00000153012), LGI4 (ENSG00000153902), LRRC52 (ENSG00000162763), ELFN2 (ENSG00000166897), LGI3 (ENSG00000168481), LRG1 (ENSG00000171236), CPN2 (ENSG00000178772), LRIT3 (ENSG00000183423), LRRC26 (ENSG00000184709), LRIG2 (ENSG00000198799), LGR4 (ENSG00000205213), ELFN1 (ENSG00000225968), LRRC24 (ENSG00000254402), TRIL (ENSG00000255690)

Protein

Protein identifiers

Leucine-rich glioma-inactivated protein 1 — O95970 (reviewed: O95970)

Alternative names: Epitempin-1

All UniProt accessions (13): O95970, A0A0D9SFE3, A0A0D9SFH6, A0A0D9SFS5, A0A0D9SFU4, A0A0S2Z4S7, A0A0S2Z4X3, A0A1B0GTM5, A0A1B0GUD3, A0A1B0GV33, A0A1B0GVF6, A0A1B0GVP2, A0A1B0GWB4

UniProt curated annotations — full annotation on UniProt →

Function. Regulates voltage-gated potassium channels assembled from KCNA1, KCNA4 and KCNAB1. It slows down channel inactivation by precluding channel closure mediated by the KCNAB1 subunit. Ligand for ADAM22 that positively regulates synaptic transmission mediated by AMPA-type glutamate receptors. Plays a role in suppressing the production of MMP1/3 through the phosphatidylinositol 3-kinase/ERK pathway. May play a role in the control of neuroblastoma cell survival.

Subunit / interactions. Oligomer. Interacts with KCNA1 within a complex containing KCNA1, KCNA4 and KCNAB1. Part of a complex containing ADAM22, DLG4/PSD95 and CACNG2/Stargazin. Can bind to ADAM11 and ADAM23.

Subcellular location. Secreted. Synapse. Cytoplasm Golgi apparatus. Cytoplasm Endoplasmic reticulum. Cytoplasm.

Tissue specificity. Predominantly expressed in neural tissues, especially in brain. Expression is reduced in low-grade brain tumors and significantly reduced or absent in malignant gliomas. Expressed in the occipital cortex and hippocampus; higher amounts are observed in the parietal and frontal cortices, putamen, and, particularly, in the temporal neocortex, where it is between 3 and 5 times more abundant than in the hippocampus (at protein level). Expression is absent in the cerebellum. Abundantly expressed in the occipital cortex and weakly expressed in the hippocampus (at protein level).

Post-translational modifications. Glycosylated.

Disease relevance. Epilepsy, familial temporal lobe, 1 (ETL1) [MIM:600512] A focal form of epilepsy characterized by recurrent seizures that arise from foci within the temporal lobe. Seizures are usually accompanied by sensory symptoms, most often auditory in nature. The disease is caused by variants affecting the gene represented in this entry.

Induction. Down-regulated in neuroblastoma cells.

Isoforms (3)

UniProt ID	Names	Canonical?
O95970-1	1	yes
O95970-2	2
O95970-3	3

RefSeq proteins (3): NP_001295204, NP_001295205, NP_005088* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR005492	EPTP	Repeat
IPR009039	EAR	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR051295	LGI_related	Family

Pfam: PF03736, PF13855

UniProt features (97 total): strand 42, sequence variant 17, repeat 10, turn 10, helix 5, glycosylation site 3, splice variant 3, mutagenesis site 3, domain 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5Y30	X-RAY DIFFRACTION	1.78
5Y2Z	X-RAY DIFFRACTION	2.67
9KZC	ELECTRON MICROSCOPY	2.78
8HQ2	X-RAY DIFFRACTION	2.93
8Y6B	X-RAY DIFFRACTION	3.49
9KZT	ELECTRON MICROSCOPY	3.79
8HQ1	X-RAY DIFFRACTION	4.17
8HPY	X-RAY DIFFRACTION	5.87
5Y31	X-RAY DIFFRACTION	7.12

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95970-F1	92.81	0.89

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (3): 192, 277, 422

Mutagenesis-validated functional residues (3):

Position	Phenotype
192	affects glycosylation; when associated with q-277 and q-422. loss of protein secretion; when associated with q-277 and q
277	affects glycosylation; when associated with q-192 and q-422. loss of protein secretion; when associated with q-192 and q
422	affects glycosylation; when associated with q-192 and q-277. loss of protein secretion; when associated with q-192 and q

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5682910	LGI-ADAM interactions
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 249 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, MORF_ITGA2, RRAGTTGT_UNKNOWN, LEE_NEURAL_CREST_STEM_CELL_DN, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_GROWTH, GOBP_NEUROGENESIS, CAGCTG_AP4_Q5, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, MORF_RAD51L3, GOBP_CELL_CELL_SIGNALING, NKX61_01, EVI1_05, FREAC3_01

GO Biological Process (7): nervous system development (GO:0007399), axon guidance (GO:0007411), positive regulation of cell growth (GO:0030307), neuron projection development (GO:0031175), positive regulation of synaptic transmission (GO:0050806), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645), signal transduction (GO:0007165)

GO Molecular Function (3): signaling receptor binding (GO:0005102), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (10): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), dendrite (GO:0030425), synaptic cleft (GO:0043083), axon initial segment (GO:0043194), glutamatergic synapse (GO:0098978), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
system development	1
axonogenesis	1
neuron projection guidance	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
neuron development	1
plasma membrane bounded cell projection organization	1
chemical synaptic transmission	1
positive regulation of cell communication	1
positive regulation of signaling	1
modulation of chemical synaptic transmission	1
protein-containing complex localization	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
protein localization to postsynaptic specialization membrane	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein binding	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
binding	1
intracellular anatomical structure	1
neuron projection	1
dendritic tree	1
extracellular region	1
main axon	1
synapse	1
cell junction	1

Protein interactions and networks

STRING

980 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LGI1	ADAM22	Q9P0K1	999
LGI1	ADAM23	O75077	996
LGI1	ADAM28	Q9UKQ2	994
LGI1	CNTNAP2	Q9UHC6	994
LGI1	KCNA1	Q09470	989
LGI1	CNTN2	P78432	914
LGI1	DLG4	P78352	904
LGI1	KCNAB1	Q14722	884
LGI1	IGLON5	A6NGN9	881
LGI1	PNMA2	Q9UL42	877
LGI1	DPP10	Q8N608	873
LGI1	DPYSL5	Q9BPU6	872
LGI1	DPP6	P42658	871
LGI1	AMPH	P49418	870
LGI1	CACNG2	Q9Y698	810

IntAct

3 interactions, top by confidence:

A	B	Type	Score
LGI1	APAF1	psi-mi:“MI:0914”(association)	0.350
CLIC6	LGI1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (55): LGI1 (Affinity Capture-MS), LGI1 (Affinity Capture-Western), LGI1 (Affinity Capture-Western), LGI1 (Affinity Capture-MS), FUT11 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), STK39 (Affinity Capture-MS), CAMK4 (Affinity Capture-MS), LRP5 (Affinity Capture-MS), DUSP14 (Affinity Capture-MS), ARSK (Affinity Capture-MS), RAD17 (Affinity Capture-MS), EOGT (Affinity Capture-MS), OXSR1 (Affinity Capture-MS), BANP (Affinity Capture-MS)

ESM2 similar proteins: A4IGL7, D3ZB51, E9PZ19, O75882, O94779, O95970, P00533, P02469, P07942, P13590, P15209, P24503, P24786, P33150, P39038, P55245, P55283, P68500, P97300, P97527, P97546, Q01279, Q01973, Q03351, Q16288, Q16620, Q1EGL2, Q3B7N0, Q3UQ28, Q5IFJ9, Q5IS37, Q5IS82, Q5R945, Q63604, Q6IS24, Q6VNS1, Q7TPD3, Q7TT15, Q8K4Y5, Q8N475

Diamond homologs: O95970, P24014, Q1EGL0, Q1EGL1, Q1EGL2, Q4R4H3, Q5E9T6, Q5R945, Q6EMK4, Q8K1S1, Q8K406, Q8K4Y5, Q8K4Z0, Q8N0V4, Q8N135, Q8N145, Q9CZT5, Q9JIA1, Q9WVC1, P70193, A3KNN3, A6H789, A6H793, A6NJW4, A8WHP9, C3YZ59, O60602, P21956, P59034, P59035, P70490, P79385, P86468, P98164, Q45R42, Q4R8Y9, Q5PQV5, Q6DF55, Q6P3Y9, Q6PEZ8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

573 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	28
Uncertain significance	275
Likely benign	160
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069952	NM_005097.4(LGI1):c.446_449del (p.Asn149fs)	Pathogenic
1071970	NC_000010.10:g.(?95517882)(95537394_?)del	Pathogenic
1075145	NM_005097.4(LGI1):c.795G>A (p.Trp265Ter)	Pathogenic
1075701	NM_005097.4(LGI1):c.1118T>A (p.Leu373Ter)	Pathogenic
1202118	NM_005097.4(LGI1):c.329del (p.Ala110fs)	Pathogenic
1365772	NM_005097.4(LGI1):c.1252C>T (p.Gln418Ter)	Pathogenic
1410458	NM_005097.4(LGI1):c.1599dup (p.Asn534Ter)	Pathogenic
1455204	NM_005097.4(LGI1):c.988C>T (p.Arg330Ter)	Pathogenic
1458021	NM_005097.4(LGI1):c.443dup (p.Asn148fs)	Pathogenic
1527920	NM_005097.4(LGI1):c.1442del (p.Pro481fs)	Pathogenic
1701149	NM_005097.4(LGI1):c.606_607delinsA (p.Pro204fs)	Pathogenic
2000198	NM_005097.4(LGI1):c.1396C>T (p.Gln466Ter)	Pathogenic
208125	NM_005097.4(LGI1):c.1013T>C (p.Phe338Ser)	Pathogenic
208478	NM_005097.4(LGI1):c.1420C>T (p.Arg474Ter)	Pathogenic
208479	NC_000010.11:g.(93704377_?)_(?_93785620)del	Pathogenic
2425295	NC_000010.10:g.(?95517902)(95518136_?)del	Pathogenic
2735458	NM_005097.4(LGI1):c.598del (p.Cys200fs)	Pathogenic
2746608	NM_005097.4(LGI1):c.1104C>A (p.Tyr368Ter)	Pathogenic
2756254	NM_005097.4(LGI1):c.600C>A (p.Cys200Ter)	Pathogenic
2839772	NM_005097.4(LGI1):c.416del (p.Lys139fs)	Pathogenic
3244840	NC_000010.10:g.(?95517902)(95518608_?)del	Pathogenic
3777298	NM_005097.4(LGI1):c.1636_1637del (p.Gln546fs)	Pathogenic
408590	NM_005097.4(LGI1):c.1128G>A (p.Trp376Ter)	Pathogenic
408592	NM_005097.4(LGI1):c.688C>T (p.Gln230Ter)	Pathogenic
464744	NM_005097.4(LGI1):c.1256T>G (p.Leu419Ter)	Pathogenic
4686647	NM_005097.4(LGI1):c.245T>C (p.Ile82Thr)	Pathogenic
4686648	NM_005097.4(LGI1):c.143G>T (p.Cys48Phe)	Pathogenic
4686650	NM_005097.4(LGI1):c.1570T>C (p.Ser524Pro)	Pathogenic
4686651	NM_005097.4(LGI1):c.1672T>G (p.Ter558Gly)	Pathogenic
4733625	NM_005097.4(LGI1):c.942del (p.Phe314fs)	Pathogenic

SpliceAI

1128 predictions. Top by Δscore:

Variant	Effect	Δscore
10:93777451:G:GG	donor_gain	1.0000
10:93790169:GT:G	donor_gain	1.0000
10:93790178:GACC:G	donor_gain	1.0000
10:93790226:G:GT	donor_gain	1.0000
10:93793182:GCAG:G	acceptor_loss	1.0000
10:93793184:A:AG	acceptor_gain	1.0000
10:93793185:G:GA	acceptor_gain	1.0000
10:93793185:GA:G	acceptor_gain	1.0000
10:93793185:GAA:G	acceptor_gain	1.0000
10:93793348:CAGG:C	donor_loss	1.0000
10:93793349:AGGTA:A	donor_loss	1.0000
10:93793352:T:G	donor_loss	1.0000
10:93758832:G:GG	donor_gain	0.9900
10:93777615:CTT:C	donor_gain	0.9900
10:93777618:G:GG	donor_gain	0.9900
10:93790171:G:GG	donor_gain	0.9900
10:93792770:T:TA	acceptor_gain	0.9900
10:93792777:A:AG	acceptor_gain	0.9900
10:93792777:AAACT:A	acceptor_gain	0.9900
10:93792778:A:G	acceptor_gain	0.9900
10:93792908:TACAG:T	donor_loss	0.9900
10:93792909:ACAGG:A	donor_loss	0.9900
10:93792910:CAG:C	donor_loss	0.9900
10:93792912:GGTAA:G	donor_loss	0.9900
10:93792913:GTA:G	donor_loss	0.9900
10:93792914:T:G	donor_loss	0.9900
10:93793185:GAAT:G	acceptor_gain	0.9900
10:93793185:GAATT:G	acceptor_gain	0.9900
10:93758365:GCCC:G	donor_gain	0.9800
10:93758369:G:GG	donor_gain	0.9800

AlphaMissense

3690 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:93777547:T:C	F121L	1.000
10:93777548:T:G	F121C	1.000
10:93777549:C:A	F121L	1.000
10:93777549:C:G	F121L	1.000
10:93777561:C:A	N125K	1.000
10:93777561:C:G	N125K	1.000
10:93790114:C:A	N149K	1.000
10:93790114:C:G	N149K	1.000
10:93796985:T:C	C286R	1.000
10:93758307:T:A	C55S	0.999
10:93758308:G:C	C55S	0.999
10:93758828:T:C	L95P	0.999
10:93758831:T:C	L96S	0.999
10:93777423:T:C	F111S	0.999
10:93777423:T:G	F111C	0.999
10:93777450:T:C	L120S	0.999
10:93777548:T:C	F121S	0.999
10:93777554:A:T	E123V	0.999
10:93777559:A:T	N125Y	0.999
10:93777617:T:C	L144S	0.999
10:93790100:A:C	S145R	0.999
10:93790102:C:A	S145R	0.999
10:93790102:C:G	S145R	0.999
10:93790104:T:A	L146H	0.999
10:93790104:T:C	L146P	0.999
10:93792758:T:A	N173K	0.999
10:93792758:T:G	N173K	0.999
10:93792769:G:A	C177Y	0.999
10:93792770:T:G	C177W	0.999
10:93792837:T:A	C200S	0.999

dbSNP variants (sampled 300 via entrez): RS1000046850 (10:93760546 G>A,T), RS1000115319 (10:93766590 C>T), RS1000297464 (10:93766245 T>C), RS1000304278 (10:93784461 T>G), RS1000310255 (10:93793824 T>A), RS1000361651 (10:93772123 A>C), RS1000515178 (10:93756165 A>AC), RS1000641793 (10:93783312 C>T), RS1000685650 (10:93781266 G>T), RS1000692846 (10:93770859 A>G), RS1000758020 (10:93779856 G>A), RS1000769833 (10:93789036 A>G), RS1000781441 (10:93798299 G>A), RS1000835218 (10:93798653 G>A), RS1001045024 (10:93791619 C>A,T)

Disease associations

OMIM: gene MIM:604619 | disease phenotypes: MIM:600512, MIM:606170, MIM:621475

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant epilepsy with auditory features	Definitive	Autosomal dominant
epilepsy, familial temporal lobe, 1	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal dominant epilepsy with auditory features	Definitive	AD

Mondo (5): autosomal dominant epilepsy with auditory features (MONDO:0010898), epilepsy, familial temporal lobe, 1 (MONDO:0700090), genitopatellar syndrome (MONDO:0011640), developmental and epileptic encephalopathy 121 (MONDO:0980966), intellectual disability (MONDO:0001071)

Orphanet (3): Epilepsy with auditory features (Orphanet:101046), Genitopatellar syndrome (Orphanet:85201), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

100 total (30 of 100 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000431	Wide nasal bridge
HP:0000496	Abnormality of eye movement
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0000817	Reduced eye contact
HP:0001076	Glabellar hemangioma
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001699	Sudden death

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST006297_3	Response to perphenazine in schizophrenia	5.000000e-06
GCST006996_2	Cerebrospinal AB1-42 levels in mild cognitive impairment	3.000000e-07
GCST007012_3	Cerebrospinal fluid AB1-42 levels	7.000000e-06
GCST009174_2	Response to (pegylated) interferon in chronic hepatitis B	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0007859	response to interferon

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C537297	Autosomal Dominant Lateral Temporal Lobe Epilepsy (supp.)
C565255	Genitopatellar Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	6
methylmercuric chloride	increases expression	3
Tretinoin	decreases expression, increases expression	2
pirinixic acid	affects binding, increases activity, increases expression	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Arsenic Trioxide	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Cisplatin	affects expression	1
Lead	affects expression	1
Methylcholanthrene	affects binding, increases reaction	1
Rotenone	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Palmitic Acid	increases expression	1

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1TG	Abcam U-87MG LGI1 KO	Cancer cell line	Male
CVCL_QX85	CIRAi002-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders