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Intellectual disability

Gene: GLS

Amber List (moderate evidence)
GLS (glutaminase)
EnsemblGeneIds (GRCh38): ENSG00000115419
EnsemblGeneIds (GRCh37): ENSG00000115419
OMIM: 138280, Gene2Phenotype
GLS is in 8 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Added 'watchlist_MOI' tag to highlight monoallelic phenotype (MIM# 618339) which is also relevant to this panel, but as there is only a single case reported to date this is not yet sufficient to update the MOI.
Created: 11 Nov 2021, 10:34 a.m. | Last Modified: 11 Nov 2021, 10:34 a.m.
Panel Version: 3.1451
Comment on list classification: New gene added by Zornitza Stark. Early developmental delay, which preceded other progressive neurological concerns, was reported in the three unrelated cases from PMID:30970188. Following discussion with Helen Brittain (Genomics England Clinical Team) it was agreed that this is sufficient for inclusion on this panel.

However, detection of the 5' UTR triplet expansion must first be internally validated for the interpretation pipeline. In the meantime, rating Amber but will raise the STR for validation with the Rare Disease team.
Created: 18 Jan 2021, 6:09 p.m. | Last Modified: 18 Jan 2021, 6:09 p.m.
Panel Version: 3.713
Comment on mode of inheritance: As evidence for pathogenicity of monoallelic variants is limited (currently only 1 case), MOI will remain as 'Biallelic' until further cases emerge that support an association between monoallelic variants and disease.
Created: 18 Jan 2021, 5:38 p.m. | Last Modified: 18 Jan 2021, 5:38 p.m.
Panel Version: 3.710
One case reported with a de novo (i.e. monoallelic) gain-of-function variant, associated with profound developmental delay, infantile cataract, skin abnormalities, and glutamate excess. Functional analysis showed the variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS (PMID: 30239721).
Created: 18 Jan 2021, 5:32 p.m. | Last Modified: 18 Jan 2021, 5:32 p.m.
Panel Version: 3.709
- PMID: 30970188 (2019) - Three unrelated cases who presented with an early-onset global developmental delay, progressive ataxia, and elevated levels of glutamine. One patient also showed cerebellar atrophy.

All 3 individuals harboured a large trinucleotide (GCA) repeat expansion in the 5' UTR (length: 680-1,500-copy repeats). The repeat expansion was found in homozygosity in 1 case, and occurred in compound heterozygosity with an SNV in the other two cases (missense and frameshift variant, respectively). Functional analysis showed the repeat expansion results in reduced expression and glutaminase deficiency.
Created: 18 Jan 2021, 3:41 p.m. | Last Modified: 18 Jan 2021, 3:41 p.m.
Panel Version: 3.708

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733

Publications

Created: 18 Jan 2021, 3:41 p.m.
Last Modified: 18 Jan 2021, 3:41 p.m.
Panel version: 3.1451

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Three unrelated individuals described with compound het variants, however, note one of these is a triplet expansion in the 5' UTR.
Sources: Expert list
Created: 6 Feb 2020, 1:20 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412

Publications

Created: 6 Feb 2020, 1:20 a.m.

Panel version: 3.0

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412
  • Developmental and epileptic encephalopathy 71, OMIM:618328
  • ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339
Tags
watchlist STR watchlist_moi
OMIM
138280
Clinvar variants
Variants in GLS
Penetrance
None
Publications
Panels with this gene

History Filter Activity

17 Mar 2022, Gel status: 2

Removed Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review was removed from gene: GLS. Tag watchlist tag was added to gene: GLS.

11 Nov 2021, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339

11 Nov 2021, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag watchlist_moi tag was added to gene: GLS.

18 Jan 2021, Gel status: 2

Added Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag STR tag was added to gene: GLS. Tag for-review tag was added to gene: GLS.

18 Jan 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: gls has been classified as Amber List (Moderate Evidence).

18 Jan 2021, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685

18 Jan 2021, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733 to Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412

18 Jan 2021, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733

18 Jan 2021, Gel status: 0

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: GLS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal

6 Feb 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Zornitza Stark (Australian Genomics)

gene: GLS was added gene: GLS was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: GLS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GLS were set to 30970188 Phenotypes for gene: GLS were set to Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 Review for gene: GLS was set to GREEN