GLS

Chr 2ADAR

glutaminase

ENSG00000115419 UniProt: O94925 OMIM: 138280

The encoded mitochondrial glutaminase catalyzes the hydrolysis of glutamine to glutamate and ammonia, serving essential roles in energy metabolism, glutamate neurotransmitter synthesis in the brain, and acid-base balance in the kidney. Loss-of-function mutations cause CASGID syndrome, developmental and epileptic encephalopathy 71, and global developmental delay with progressive ataxia and elevated glutamine through both autosomal dominant and autosomal recessive inheritance patterns. The high pLI score (0.96) indicates this gene is highly intolerant to loss-of-function variants, consistent with its essential metabolic functions.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain (PubMed:30239721, PubMed:30575854, PubMed:30970188)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

CASGID syndromeMIM #618339

Developmental and epileptic encephalopathy 71MIM #618328

Global developmental delay, progressive ataxia, and elevated glutamineMIM #618412

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · glutaminase deficiency · AR · ClinGen 2021
Strong · global developmental delay, progressive ataxia, and elevated glutamine · AR · Labcorp Genetics (formerly Invitae)
Strong · infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development · AD · PanelApp Australia
Strong · developmental and epileptic encephalopathy, 71 · AR · PanelApp Australia

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

1630

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.32LOEUF

pLI 0.962

Z-score 4.69

OE 0.16 (0.09–0.32)

Highly constrained

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

Missense Constraint?

3.73Z-score

OE missense 0.41 (0.36–0.48)

133 obs / 321.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.16 (0.09–0.32)

0≤0.351.4

Missense OE?0.41 (0.36–0.48)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 6 / 36.6Missense obs/exp: 133 / 321.1Syn Z: 0.92

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

658 rare PASS variants

Rare truncating (LoF)

1 in 1,900

123 rare PASS variants

Rare synonymous (reference)

1 in 160

347 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GLS. 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 180	1 in 2,200
South Asian	~43k	1 in 110	1 in 4,300
Remaining (unassigned)	~30k	1 in 110	1 in 2,600
European (Finnish)	~27k	1 in 260	1 in 3,200
Admixed American	~22k	1 in 81	1 in 2,800
African / African American	~21k	1 in 150	1 in 2,200
East Asian	~20k	1 in 98	1 in 3,200
Ashkenazi Jewish	~13k	1 in 160	≈ 1 in 6,200
Middle Eastern	~2,884	1 in 170	≈ 1 in 2,900

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): 4 of 18 coding exons well covered in gnomAD exomes; exons 1, 2, 3, 4, 5 and 9 more marginal. Genomes: all 18.? see exons ↓