GLS

protein-coding

glutaminase, the group of Ankyrin repeat domain containing

Gene summary

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]

MANE transcript

NM_014905.5

Inheritance

AR, AD

ClinVar variants

P:21U:119B:33

Top phenotype

Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development (CASGID syndrome); Epileptic encephalopathy, early infantile, 71; Global developmental delay, progressive ataxia, and elevated glutamine

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr2:190,880,821-190,965,552

External References & Databases

Ensembl (ENSG00000115419)

Transcript & Mutation Effects

hg38 • Region Span ~84.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 71STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032678

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 71LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032678

Submitter: Ambry Genetics

glutaminase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0600001

Submitter: Ambry Genetics

glutaminase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0600001

Submitter: ClinGen

GLS was first reported in relation to autosomal recessive glutaminase deficiency in 2018 (Lynch DS, et al., 2018, PMID: 29468182). Glutaminase deficiency is characterized by refractory seizures, respiratory failure, brain abnormalities and death in the neonatal period, though milder cases with spastic ataxia-dysarthria have also been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Five unique variants (nonsense, frameshift, and missense) have been reported as well as a 5’ UTR repeat expansion (normally occurring in 8 or 16 repeats) ranging from 680 to 1500 repeats. Variants in this gene have been reported in six probands in 3 publications (PMIDs: 29468182, 30575854, 30970188), and segregated with disease in at least 2 additional family member. Experimentally, this gene-disease relationship is supported by its role in the production of glutamate, the main excitatory neurotransmitter in the central nervous system, including the brain stem respiratory center (PMID: 12963351) and a mouse model with partial recapitulation of disease (PMID: 16641247). In summary GLS is definitively associated with autosomal recessive glutaminase deficiency.

infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual developmentMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032685

Submitter: Ambry Genetics

global developmental delay, progressive ataxia, and elevated glutamineSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032733

Submitter: Labcorp Genetics (formerly Invitae)

infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual developmentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032685

Submitter: PanelApp Australia

global developmental delay, progressive ataxia, and elevated glutamineSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032733

Submitter: PanelApp Australia

infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual developmentLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032685

Submitter: ClinGen

*GLS* was first reported in relation to autosomal dominant infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development due to GLS hyperactivity in 2019 (Rumping L, et al., 2019, PMID: 30239721). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Two missense variants (Ser482Cys and His461Leu) have been reported from two probands in two publications (PMIDs: 30239721, 37151363). To validate enhanced catalytic activity of the Ser482Cys *GLS* variant, a HEK293 cell model with inducible expression of Ser482Cys-GLS was generated. Induction of Ser482Cys-GLS again strongly increased the glutamate/glutamine ratio (as in the patient) while induction of wild-type GLS had no effect (PMID: 30239721). Experimentally, this gene-disease relationship is supported by its role in the production of glutamate (PMID: 12963351), the resulting oxidative stress found in the patient as a consequence of glutamate excess, which contributes to the ophthalmologic phenotype (PMID: 30239721), and a zebrafish model with partial recapitulation of disease (PMID: 30239721). In summary, there is limited 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 relationship was originally approved by the Aminoacidopathy GCEP on July 9, 2021. It was recurated on July 26, 2024 with new evidence (PMID: 37151363) resulting in no change of classificaiton. Of note, two inborn errors of metabolism are caused by opposite defects in *GLS*. *GLS* deficiency due to loss‐of‐function [OMIM #618328/618412] in biallelic variants results in elevated glutamine plasma levels and a phenotypic spectrum of ataxia, optic atrophy, developmental delay, neonatal seizures, and neonatal death. The opposite biochemical defect has been described with *GLS* hyperactivity [OMIM #618339] caused by de novo heterozygous missense variants in *GLS.* Per ClinGen Lumping and Splitting criteria these were considered two seperate disease entities based on differences in moleclar mechanism, phenotype, and inheritance pattern. The autosomal recessive GLS deficiency was curated seperately.

infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual developmentLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032685

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Manifestation: Biochemical; Dermatologic; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Global developmental delay, progressive ataxia, and elevated glutamine is caused by triplet repeat expansion upstream of the GLS gene

Refs: 30239721; 30575854; 30970188; 35803560; 37151363

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLS variants in ClinVar

9 Conditions Cataloged

not providedTotal: 70

Inborn genetic diseasesTotal: 61

not specifiedTotal: 28

GLS-related disorderTotal: 22

Developmental and epileptic encephalopathy, 71Total: 9

Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual developmentTotal: 6

Global developmental delay, progressive ataxia, and elevated glutamineTotal: 4

Autosomal recessive GLS-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014905.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	25 clinvar	1 clinvar	28
missense	4 clinvar	6 clinvar	107 clinvar	5 clinvar	2 clinvar	124
nonsense	3 clinvar	1 clinvar				4
start loss			1 clinvar			1
frameshift	4 clinvar	1 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)		2 clinvar	8 clinvar			10
Total	11	10	119	30	3	173

Highest pathogenic variant AF is 7.177164e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014905.5	RefSeq	NP_055720.3	18	MANE Select
ENST00000320717.8	Ensembl	ENSP00000317379.3	18	MANE Select
NM_001256310.2	RefSeq	NP_001243239.1	15	Standard
NM_001437282.1	RefSeq	NP_001424211.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Central carbon metabolism in cancer - Homo sapiens (human)
GABAergic synapse - Homo sapiens (human)
Glutamatergic synapse - Homo sapiens (human)
D-Glutamine and D-glutamate metabolism - Homo sapiens (human)

Biological Process

suckling behavior
regulation of respiratory gaseous exchange by neurological system process
glutamate biosynthetic process
glutamine catabolic process
chemical synaptic transmission

Molecular Function

glutaminase activity
protein binding

Cellular Component

mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320717
Coding exons: 18
Length: 84726
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125735
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.73	133	321	0.414	0.0000151	4330
Missense (PolyPhen)		16	86.415	0.18515		1095
Synonymous	0.919	102	115	0.891	0.00000557	1292
Loss of Function	4.69	6	36.6	0.164	0.00000209	445

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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 in the brain. Isoform 2 lacks catalytic activity.;

Intolerance Scores

LoFtool: 0.369
RVIS EVS: 0.15
RVIS percentile EVS: 64.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.950

Gene Damage Prediction

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