GeneBe

GLUL

protein-coding

glutamate-ammonia ligase

Gene summary

The protein encoded by this gene belongs to the glutamine synthetase family. It catalyzes the synthesis of glutamine from glutamate and ammonia in an ATP-dependent reaction. This protein plays a role in ammonia and glutamate detoxification, acid-base homeostasis, cell signaling, and cell proliferation. Glutamine is an abundant amino acid, and is important to the biosynthesis of several amino acids, pyrimidines, and purines. Mutations in this gene are associated with congenital glutamine deficiency, and overexpression of this gene was observed in some primary liver cancer samples. There are six pseudogenes of this gene found on chromosomes 2, 5, 9, 11, and 12. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

Previous symbols:
  • GLNS

MANE transcript

NM_001033044.4

Inheritance

AR, AD

ClinVar variants

P:14U:89B:38

Top phenotype

Glutamine deficiency, congenital

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:182,378,098-182,392,206

External References & Databases

Ensembl (ENSG00000135821)NCBI Gene (2752)OMIM (138290)HGNC:4341GenCCUniProt (P15104)AlphaFoldClinVar (GLUL)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~14.1 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital brain dysgenesis due to glutamine synthetase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012393

Submitter: Orphanet

congenital brain dysgenesis due to glutamine synthetase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012393

Submitter: Ambry Genetics

congenital brain dysgenesis due to glutamine synthetase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012393

Submitter: ClinGen

*GLUL* was first reported in relation to autosomal recessive congenital brain dysgenesis due to glutamine synthetase deficiency in 2005 (Häberle J, et al., PMID: 16267323). At least 4 unique variants (all missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 5 probands in 4 publications (PMIDs: 16267323, 21353613, 30440076, 33150193). This gene-disease association is supported by its biochemical function as glutamine synthetase (PMID: 5336023) and several conditional knockout mouse models with partial recapitulation of disease (PMIDs: 25870278, 20140959, 30053506). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was previously evaluated by the Aminoacidopathy GCEP on 09/25/2020. It was reevaluated on 10/14/2022 with identification of one new proband (and affected sibling) in PMID: 33150193. It was reevaluated again on 12/9/2024 with no new evidence identified. As a result of this reevaluation, the classification remained Moderate. Of note, a novel disease entity was reported in relation to *GLUL* in 2024 (PMID: 38579670), glutamine synthetase stabilization disorder (GSSD) was reported due to monoallelic *de novo* dominant negative variants and will be considered seperately from this recessive loss of function curation.

developmental and epileptic encephalopathy 116STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0970945

Submitter: PanelApp Australia

congenital brain dysgenesis due to glutamine synthetase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012393

Submitter: G2P

congenital brain dysgenesis due to glutamine synthetase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012393

Submitter: PanelApp Australia

congenital brain dysgenesis due to glutamine synthetase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012393

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy 116STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0970945

Submitter: Ambry Genetics

genetic developmental and epileptic encephalopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

*GLUL* was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2024 (Jones et al., PMID: 38579670). This condition is characterized by severe developmental delay, seizures, and white matter abnormalities with normal plasma and cerebrospinal fluid biochemistry. Of note, this gene has also been implicated in autosomal recessive congenital brain dysgenesis due to glutamine synthetase deficiency. This condition has been assessed separately by the Aminoacidopathy GCEP. [https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d71d7866-437d-48bd-8a98-21e67abdd917-2024-12-13T170000.000Z?page=1&size=25&search=](https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d71d7866-437d-48bd-8a98-21e67abdd917-2024-12-13T170000.000Z?page=1&size=25&search=). Six start-loss variants have been reported in nine probands from one publication (PMID: 38579670). Evidence supporting this gene-disease relationship includes case-level data and experimental data determining the functional effect of variants. The functional assays discussed in this curation show stable enzymatic activity of the resultant transcript starting at methionine 18 in vitro and insensitivity to negative feedback from high glutamine levels in dermal fibroblasts from affected individuals (PMID: 38579670). The mechanism of pathogenicity appears to be gain of function due to loss of sensitivity to negative feedback (PMID: 38579670). In summary, there is moderate evidence to support the relationship between *GLUL* and autosomal dominant developmental and epileptic encephalopathy. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy GCEP on January 7, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Glutamine deficiency, congenitalAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: Supplementation with glutamine has been reported as resulting in clinical (measured by alertness) and electroencephalogram-documented improvements

Refs: 16267323; 21353613; 22830360; 38579670Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLUL variants in ClinVar

11 Conditions Cataloged
Congenital brain dysgenesis due to glutamine synthetase deficiencyTotal: 122
not providedTotal: 41
Inborn genetic diseasesTotal: 25
Developmental and epileptic encephalopathy 116Total: 13
GLUL-related disorderTotal: 11
not specifiedTotal: 10
Glutamine synthetase stabilization disorderTotal: 6
EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001033044.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
35
clinvar
2
clinvar
 39
missense
3
clinvar
3
clinvar
78
clinvar
1
clinvar
 85
nonsense
2
clinvar
 2
start loss
1
clinvar
3
clinvar
1
clinvar
 5
frameshift
1
clinvar
4
clinvar
 5
splice donor/acceptor (+/-2bp)
3
clinvar
2
clinvar
 5
Total5989362141

Highest pathogenic variant AF is 0.0000030980968

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001033044.4RefSeqNP_001028216.16MANE Select
ENST00000331872.11EnsemblENSP00000356537.66MANE Select
NM_001033056.4RefSeqNP_001028228.16Standard
NM_002065.7RefSeqNP_002056.26Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
  • GABAergic synapse - Homo sapiens (human)
  • Glutamatergic synapse - Homo sapiens (human)
  • Necroptosis - Homo sapiens (human)
  • Nitrogen metabolism - Homo sapiens (human)

Biological Process

  • neurotransmitter uptake
  • angiogenesis
  • glutamate catabolic process
  • glutamine biosynthetic process
  • cell population proliferation

Molecular Function

  • magnesium ion binding
  • glutamate-ammonia ligase activity
  • protein binding
  • ATP binding
  • glutamate binding

Cellular Component

  • nucleus
  • mitochondrion
  • rough endoplasmic reticulum
  • cytosol
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000311223
Coding exons
6
Length
10503
Individuals with no LoFs
125746
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125748
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.601562240.6980.00001482473
Missense (PolyPhen)2473.3890.32702920
Synonymous-1.399579.31.200.00000485706
Loss of Function3.72016.10.008.60e-7192

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: This enzyme has 2 functions: it catalyzes the production of glutamine and 4-aminobutanoate (gamma-aminobutyric acid, GABA), the latter in a pyridoxal phosphate-independent manner (By similarity). Essential for proliferation of fetal skin fibroblasts. {ECO:0000250, ECO:0000269|PubMed:18662667}.;
Disease
DISEASE: Congenital systemic glutamine deficiency (CSGD) [MIM:610015]: Rare developmental disorder with severe brain malformation resulting in multi-organ failure and neonatal death. Glutamine is largely absent from affected patients serum, urine and cerebrospinal fluid. {ECO:0000269|PubMed:16267323}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.788

Intolerance Scores

RVIS EVS
-0.43
RVIS percentile EVS
25.15

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.850

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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