GLUL

glutamate-ammonia ligase

Basic information

Region (hg38): 1:182378098-182392206

Previous symbols: [ "GLNS" ]

Links

ENSG00000135821 ∙ NCBI:2752 ∙ OMIM:138290 ∙ HGNC:4341 ∙ Uniprot:P15104 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital brain dysgenesis due to glutamine synthetase deficiency (Definitive), mode of inheritance: AR
• congenital brain dysgenesis due to glutamine synthetase deficiency (Moderate), mode of inheritance: AR
• congenital brain dysgenesis due to glutamine synthetase deficiency (Strong), mode of inheritance: AR
• congenital brain dysgenesis due to glutamine synthetase deficiency (Supportive), mode of inheritance: AR
• congenital brain dysgenesis due to glutamine synthetase deficiency (Moderate), mode of inheritance: AR
• (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Glutamine deficiency, congenital	AR	Biochemical	Supplementation with glutamine has been reported as resulting in clinical (measured by alertness) and electroencephalogram-documented improvements	Biochemical; Neurologic	16267323; 21353613; 22830360; 38579670

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GLUL gene.

• Congenital brain dysgenesis due to glutamine synthetase deficiency (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GLUL gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	21	3	26
missense		1	42	1		44
nonsense			1			1
start loss		1	2			3
frameshift	1					1
inframe indel			2			2
splice donor/acceptor (+/-2bp)			2			2
splice region			1	3		4
non coding			80	29	30	139
Total	1	2	131	51	33

Variants in GLUL

This is a list of pathogenic ClinVar variants found in the GLUL region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-182381714-G-C		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182381761-C-G		Congenital brain dysgenesis due to glutamine synthetase deficiency	Benign (Jan 12, 2018)
1-182381769-G-A		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182381774-C-G		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182381774-C-T		Congenital brain dysgenesis due to glutamine synthetase deficiency	Benign (Jan 13, 2018)
1-182381801-G-T		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182381834-G-A		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182381850-C-G		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Feb 09, 2018)
1-182381889-T-C		Congenital brain dysgenesis due to glutamine synthetase deficiency	Benign (Jan 12, 2018)
1-182381911-C-A		Congenital brain dysgenesis due to glutamine synthetase deficiency	Likely benign (Jan 13, 2018)
1-182381942-G-T		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182382040-C-T		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182382092-G-A		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 12, 2018)
1-182382098-G-A		Congenital brain dysgenesis due to glutamine synthetase deficiency	Benign (Jan 13, 2018)
1-182382101-A-T		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182382173-G-A		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182382202-T-C		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182382233-G-A		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182382275-A-T		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182382277-G-A		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 13, 2018)
1-182382287-A-G		Congenital brain dysgenesis due to glutamine synthetase deficiency	Benign (Jan 13, 2018)
1-182382330-G-GC		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jun 14, 2016)
1-182382331-C-T		Congenital brain dysgenesis due to glutamine synthetase deficiency	Likely benign (Jan 12, 2018)
1-182382384-C-A		Congenital brain dysgenesis due to glutamine synthetase deficiency	Likely benign (Apr 27, 2017)
1-182382411-C-T		Congenital brain dysgenesis due to glutamine synthetase deficiency	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GLUL	protein_coding	protein_coding	ENST00000311223	6	10503

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.996	0.00430	125746	0	2	125748	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.60	156	224	0.698	0.0000148	2473
Missense in Polyphen		24	73.389	0.32702		920
Synonymous	-1.39	95	79.3	1.20	0.00000485	706
Loss of Function	3.72	0	16.1	0.00	8.60e-7	192

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000880	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Arginine biosynthesis - Homo sapiens (human);Glyoxylate and dicarboxylate metabolism - Homo sapiens (human);2-Hydroxyglutric Aciduria (D And L Form);Ammonia Recycling;Homocarnosinosis;Hyperinsulinism-Hyperammonemia Syndrome;Succinic semialdehyde dehydrogenase deficiency;4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency;Glutamate Metabolism;Astrocytic Glutamate-Glutamine Uptake And Metabolism;TNF alpha Signaling Pathway;Amino Acid metabolism;Glutamate Glutamine metabolism;Metabolism of amino acids and derivatives;Metabolism;glutamine biosynthesis;Neuronal System;glutamate dependent acid resistance;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;Arginine Proline metabolism;GABA shunt;Neurotransmitter uptake and metabolism In glial cells;Transmission across Chemical Synapses;Amino acid synthesis and interconversion (transamination) (Consensus)

Recessive Scores

• pRec: 0.788

Intolerance Scores

• rvis_EVS: -0.43
• rvis_percentile_EVS: 25.15

Haploinsufficiency Scores

• pHI: 0.287
• hipred: Y
• hipred_score: 0.825
• ghis: 0.556

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.850

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Glul
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: neurotransmitter uptake;angiogenesis;glutamate catabolic process;glutamine biosynthetic process;cell population proliferation;cellular amino acid biosynthetic process;cellular response to starvation;response to glucose;regulation of endothelial cell migration;protein palmitoylation;ammonia assimilation cycle;positive regulation of insulin secretion;positive regulation of epithelial cell proliferation;protein homooligomerization;positive regulation of synaptic transmission, glutamatergic;regulation of sprouting angiogenesis
• Cellular component: nucleus;mitochondrion;rough endoplasmic reticulum;cytosol;plasma membrane;protein-containing complex;perikaryon;myelin sheath;axon terminus;extracellular exosome;glial cell projection
• Molecular function: magnesium ion binding;glutamate-ammonia ligase activity;protein binding;ATP binding;glutamate binding;protein-cysteine S-palmitoyltransferase activity;manganese ion binding;identical protein binding;dynein light chain binding