GLS

Chr 2

glutaminase

Also known as: AAD20, CASGID, DEE71, EIEE71, GAC, GAM, GDPAG, GLS1

NCBI Gene: 2744 ENSG00000115419 UniProt: O94925

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes the K-type mitochondrial glutaminase. The encoded protein is an phosphate-activated amidohydrolase that catalyzes the hydrolysis of glutamine to glutamate and ammonia. This protein is primarily expressed in the brain and kidney plays an essential role in generating energy for metabolism, synthesizing the brain neurotransmitter glutamate and maintaining acid-base balance in the kidney. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtDevelopmental and epileptic encephalopathy 71

UniProtCASGID syndrome

UniProtGlobal developmental delay, progressive ataxia, and elevated glutamine

Clinical highlights

Gene-disease validity (ClinGen)

glutaminase deficiency · ARDefinitivesufficient evidence for diagnostic panels2 gene-disease associations curated in total

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

1511

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.32

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

📖

GeneReview available — GLS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

GLS · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — GLS

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Advanced Bladder CarcinomaAdvanced Genitourinary System CarcinomaMetastatic Bladder Carcinoma

Testing Olaparib in Patients With Advanced or Metastatic (Cancer That Has Spread) Bladder Cancer and Other Genitourinary Tumors With DNA-Repair Genetic Changes

ACTIVE NOT RECRUITING

NCT03375307Phase PHASE2National Cancer Institute (NCI)Started 2020-11-03

Biopsy ProcedureBiospecimen CollectionBone Marrow Biopsy

Fabry Disease

Natural History in Fabry Disease With IVS4+919G>A Mutations

ACTIVE NOT RECRUITING

NCT07506083Chinese University of Hong KongStarted 2022-10-20

Advanced Malignant Solid NeoplasmMetastatic Malignant Solid NeoplasmNF1 Mutation Positive Malignant Peripheral Nerve Sheath Tumor

Testing Whether Cancers With Specific Mutations Respond Better to Glutaminase Inhibitor, Telaglenastat Hydrochloride, Anti-Cancer Treatment, BeGIN Study

ACTIVE NOT RECRUITING

NCT03872427Phase PHASE2National Cancer Institute (NCI)Started 2019-12-14

Biospecimen CollectionComputed TomographyMagnetic Resonance Imaging

Stage II Breast CancerStage IIIA Breast Cancer

Comparison of Axillary Lymph Node Dissection With Axillary Radiation for Patients With Node-Positive Breast Cancer Treated With Chemotherapy

ACTIVE NOT RECRUITING

NCT01901094Phase PHASE3Alliance for Clinical Trials in OncologyStarted 2014-02-24

Axillary Lymph Node Dissection (ALND)Nodal Radiation TherapyAxillary Radiation Therapy

Breast Ductal Carcinoma In SituInvasive Breast CarcinomaStage II Breast Cancer AJCC v6 and v7

Breast Cancer WEight Loss Study (BWEL Study)

ACTIVE NOT RECRUITING

NCT02750826Phase PHASE3Alliance for Clinical Trials in OncologyStarted 2016-09-16

Health Education ProgramWeight Loss Intervention

Advanced Malignant Solid NeoplasmMetastatic Malignant Solid NeoplasmUnresectable Malignant Solid Neoplasm

Testing the Combination of the Anti-cancer Drugs ZEN003694 (ZEN-3694) and Talazoparib in Patients With Advanced Solid Tumors, The ComBET Trial

RECRUITING

NCT05327010Phase PHASE2National Cancer Institute (NCI)Started 2022-11-14

BET Bromodomain Inhibitor ZEN-3694Biopsy ProcedureBiospecimen Collection

Brain Injuries

The Gut-Brain Axis During Neurorehabilitation; Prebiotic Treatment to Alter the Gut Microbiome and Neurologic Symptoms

RECRUITING

NCT06607523Phase NAThe University of Texas Medical Branch, GalvestonStarted 2025-03-06

Inulin

Breast CancerCognitive Impairments

Cognitive Training for Cancer Related Cognitive Impairment in Breast Cancer Survivors

ACTIVE NOT RECRUITING

NCT05896189Phase NANRG OncologyStarted 2024-02-29

Arm 1: Computerized Cognitive Training-Global Stimulation GamesArm 2: Computerized Cognitive Training-Neuroplasticity Games

Acute Intermittent PorphyriaHereditary CoproporphyriaVariegate Porphyria

Acute Porphyria Biomarkers for Disease Activity

ACTIVE NOT RECRUITING

NCT02935400The University of Texas Medical Branch, GalvestonStarted 2014-04-28

Hemin

AsthmaAllergic RhinitisCat Allergy

Viral Mucosal Reprogramming

RECRUITING

NCT05331170Phase PHASE2The University of Texas Medical Branch, GalvestonStarted 2023-04-27

Research Grade RG-RV

Recurrent Squamous Cell Lung CarcinomaStage IV Squamous Cell Lung Carcinoma AJCC v7

Lung-MAP: Nivolumab With or Without Ipilimumab as Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer and No Matching Biomarkers

ACTIVE NOT RECRUITING

NCT02785952Phase PHASE3SWOG Cancer Research NetworkStarted 2015-12-29

IpilimumabLaboratory Biomarker AnalysisNivolumab

AutismAutistic DisorderAutism Spectrum Disorder

Sulforaphane in a New Jersey (NJ) Population of Individuals With Autism

ACTIVE NOT RECRUITING

NCT02677051Phase PHASE2Rutgers, The State University of New JerseyStarted 2016-02

SulforaphanePlacebo

Clinical Literature

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