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.

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 121MIM #621475

Epilepsy, familial temporal lobe, 1MIM #600512

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · autosomal dominant epilepsy with auditory features · AD · ClinGen 2020

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

223

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in LGI1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 240

443 rare PASS variants

Rare truncating (LoF)

1 in 980

34 rare PASS variants

Rare synonymous (reference)

1 in 230

237 rare PASS variants

Rare missense and truncating variants are carried at similar rates in LGI1; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 250	1 in 2,200
South Asian	~43k	1 in 240	1 in 7,200
Remaining (unassigned)	~30k	1 in 310	1 in 550
European (Finnish)	~27k	1 in 510	≈ 1 in 13,000
Admixed American	~22k	1 in 150	≈ 1 in 22,000
African / African American	~21k	1 in 240	1 in 980
East Asian	~20k	1 in 150	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 1,200	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 290	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 8.? see exons ↓