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Intellectual disability

Gene: GRIA2

Green List (high evidence)

GRIA2 (glutamate ionotropic receptor AMPA type subunit 2)
EnsemblGeneIds (GRCh38): ENSG00000120251
EnsemblGeneIds (GRCh37): ENSG00000120251
OMIM: 138247, Gene2Phenotype
GRIA2 is in 2 panels

8 reviews

Rebecca Foulger (Genomics England curator)

The Green review by Konstantinos Varvagiannis on August 7th 2019 supports the current Green rating of GRIA2 on the ID panel.
Created: 15 Aug 2019, 1:08 p.m. | Last Modified: 15 Aug 2019, 1:08 p.m.
Panel Version: 2.1006

Konstantinos Varvagiannis (Other)

Green List (high evidence)

A recent publication by Salpietro et al. (2019 - PMID: 31300657) reporting on 28 unrelated individuals. The phenotype overall corresponds to a NDD disorder with DD, ID (universal feature in those with appropriate age for evaluation, relevant severity), ASD, Rett-like features and seizures (12/28). All types of variants were reported (15 missense, 2 splice-site, 1 in-frame del, 1 stopgain, 2 frameshift ones, 3 CNVs spanning GRIA2 and other genes, the latter more tolerant to LoF). The role of this gene (encoding AMPA receptor GluA2 subunit), functional studies (loss of function demonstrated for the majority of mutations, though by multiple molecular mechanisms), overlapping phenotype with disorders due to other ionotropic glutamate receptor subunit genes (eg. GRIA3/4 - ID with or without seizures), animal models (PMID cited: 8938126) are among the arguments provided.
Created: 7 Aug 2019, 5:44 p.m. | Last Modified: 7 Aug 2019, 5:44 p.m.
Panel Version: 2.996

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

Catherine Snow (Genomics England)

Green List (high evidence)

GRIA2 has been associated with ID in PMID: 31300657. The authors identified 28 unrelated individuals who had heterozygous de novo GRIA2 mutations. All individuals had experienced DD and moderate to severe ID, except 2 who had died at a young age. Epilepsy was identified in at least 10 individuals.
Multiple de-novo intragenic variants including missense (n = 15), splice-site (n = 2), in-frame deletion (n = 1), stop-gain (n = 1) and frameshift (n = 2) variants were reported. In all patients with intragenic variants they were first identified by WES, WGS or massively parallel targeted sequencing and confirmed as de-novo by trio Sanger sequencing. Also a further three patients were identified with a microdeletion involving GRIA2 using micro array analysis.

GRIA2 is currently not associated with a disease in OMIM or Gene2Phenotype and this is the first time that GRIA2 has been reported to be associated with ID but other AMPA receptors, GRIA3, and GRIA4 are Green on the ID panel.
Therefore there is now sufficient number of unrelated individuals and evidence to make GRIA2 Green.
Created: 23 Jul 2019, 1:52 p.m. | Last Modified: 23 Jul 2019, 1:54 p.m.
Panel Version: 2.969

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Louise Daugherty (Genomics England Curator)

Comment on list classification: changed to Amber until publication
Created: 30 Jul 2018, 1:52 p.m.
Comment on list classification: upgraded gene from Red to Green. In addition to the external reviewer comment this gene has been reported on for ID, even though it was only a Tier 3 variant in the ID panel.
Created: 13 Jul 2018, 9:51 a.m.
Comment on mode of inheritance: Added MOI suggested by reviewer
Created: 13 Jul 2018, 9:37 a.m.
Comment on phenotypes: Added phenotypes suggested from external expert review.
Created: 13 Jul 2018, 9:28 a.m.

Sarah Leigh (Genomics England Curator)

Not associated with phenotype in OMIM or G2P. Reported as a candidate ID gene (Grozeva 2015 PMID 26350204, Gilessen 2014 PMID 24896178). GRIA2 knockout mice displayed strong spatial working memory impairment (PMID 28725178)
Created: 6 Mar 2018, 6:46 p.m.

Caroline Wright (Sanger)

Red List (low evidence)

Jill Clayton-Smith (Manchester Centre For Genomic Medicine)

Green List (high evidence)

A LOF variant was identified in this gene in one of my patients (not listed as Tier 1 or 2 as it is still flagged up as red) and through further research I have been able to find more than 10 other individuals worldwide, some with identical phenotypes. There has been no functional work so nothing published as yet but I think it would be helpful for this gene to go on the green panel so that further patients are more likely to be identified.
Created: 19 Jun 2017, 11:56 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
epileptic encephalopathy intellectual disability stereotypic hand movements

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
Phenotypes
  • Epileptic encephalopathy intellectual disability stereotypic hand movements
Tags
watchlist
OMIM
138247
Clinvar variants
Variants in GRIA2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

23 Jul 2019, Gel status: 3

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: gria2 has been classified as Green List (High Evidence).

23 Jul 2019, Gel status: 2

Set publications

Catherine Snow (Genomics England)

Publications for gene: GRIA2 were set to 28725178; 26350204; 24896178; 22669415; 28630856

30 Jul 2018, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: gria2 has been classified as Amber List (Moderate Evidence).

13 Jul 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: gria2 has been classified as Green List (High Evidence).

13 Jul 2018, Gel status: 1

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: GRIA2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

13 Jul 2018, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: GRIA2 were set to Epileptic encephalopathy intellectual disability stereotypic hand movements

13 Jul 2018, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: GRIA2 were set to 28725178; 26350204; 24896178; 22669415; 28630856

13 Jul 2018, Gel status: 1

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: GRIA2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

12 Mar 2018, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for gene GRIA2 was set to ['28725178', '26350204', '24896178']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

GRIA2 was created by ellenmcdonagh

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

GRIA2 was added to Intellectual disabilitypanel. Sources: Expert Review Red