LGI1

Chr 10ARAD

leucine rich glioma inactivated 1

Also known as: ADLTE, ADPAEF, ADPEAF, DEE121, EPITEMPIN, EPT, ETL1, IB1099

NCBI Gene: 9211 ENSG00000108231 UniProt: O95970 OMIM: 604619

The protein regulates voltage-gated potassium channels and serves as a ligand for ADAM22 to modulate synaptic transmission mediated by AMPA-type glutamate receptors. Mutations cause autosomal dominant familial temporal lobe epilepsy and autosomal recessive developmental and epileptic encephalopathy. This gene is highly constrained against loss-of-function variants, reflecting its critical role in neuronal function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Apr 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.192 OMIM phenotypes

Clinical Summary— LGI1

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Gene-Disease Validity (ClinGen)

autosomal dominant epilepsy with auditory features · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

78 unique Pathogenic / Likely Pathogenic· 274 VUS of 573 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — LGI1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 0.999

Z-score 4.43

OE 0.04 (0.01–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.78Z-score

OE missense 0.54 (0.47–0.62)

158 obs / 291.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.54 (0.47–0.62)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 1 / 24.8Missense obs/exp: 158 / 291.6Syn Z: 0.70

This gene — mechanism propensity

0.4487th %ile

GOF

0.4875th %ile

LOF

0.67top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 69% of P/LP variants are LoF · LOEUF 0.19 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNHuman epilepsy-associated dominant-negative-truncated mutant LGI1 inhibited the seizure-induced suppression of phasic firing, increase of A-type K(+) current, and recruitment of Kv4.2 surface expression (in vivo and in vitro).1

LOFHaploinsufficiency of the leucine-rich glioma inactivated 1 (LGI1) gene is the major pathogenic basis for ADLTE, an inherited syndrome with no cure to date.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

573 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44

Likely Pathogenic34

VUS274

Likely Benign166

Benign17

Conflicting32

Pathogenic

Likely Pathogenic

274

VUS

166

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	30	9	5	0	44
Likely Pathogenic	24	7	3	0	34
VUS	1	249	21	3	274
Likely Benign	0	4	45	117	166
Benign	0	0	16	1	17
Conflicting	—				32
Total	55	269	90	121	567

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap LGI1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →