Intellectual disability - microarray and sequencing
Gene: GRIA1
Comment on list classification: There is sufficient evidence (6 unrelated cases with monoallelic inheritance and functional evidence including Xenopus models) for this gene to be promoted to GREEN at the next major review.Created: 20 Apr 2023, 10:34 a.m. | Last Modified: 20 Apr 2023, 10:34 a.m.
Panel Version: 5.67
Comment on mode of inheritance: The MOI should be monoallelic, as there is only one case identified with biallelic inheritance.Created: 20 Apr 2023, 10:31 a.m. | Last Modified: 20 Apr 2023, 10:31 a.m.
Panel Version: 5.63
Four different heterozygous variants in GRIA1 (p.Ala636Thr, p.Gly745Asp, p.Ile627Thr & p.Arg345Gln) have been identified in six unrelated individuals and they were all reported with intellectual disability, moderate to severe cognitive impairment, delayed motor development, speech impairment and behavioural issues such as anxiety, autism spectrum disorder and attention deficit hyperactivity disorder.
Homozygous variant (p.Arg377Ter) has been identified in one individual, who presented with intellectual disability, severe cognitive impairment, delayed motor development, speech impairment (non-verbal) and self-injurious behaviour.
In vitro functional studies with major GluA1-containing AMPAR subtypes carrying the GRIA1 variant mutations showed that three of the four missense variants profoundly perturb receptor function. The homozygous stop-gain variant completely destroyed the expression of GluA1-containing AMPARs. The Xenopus gria1 models also show transient motor deficits, an intermittent seizure phenotype, and a significant impairment to working memory in mutants.
This gene has also been associated with relevant phenotypes in both OMIM (MIM #619927 & MIM #619931) and Gene2Phenotype (with 'moderate' rating).Created: 20 Apr 2023, 10:23 a.m. | Last Modified: 20 Apr 2023, 10:49 a.m.
Panel Version: 5.67
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Publications
The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.Created: 11 Oct 2023, 9:34 a.m. | Last Modified: 11 Oct 2023, 9:34 a.m.
Panel Version: 5.286
Comment on list classification: Maintaining Amber rating as no new evidence has been published since previous review. Most commonly reported as a candidate gene in large screening studies with limited segregation/phenotype/functional data. Also variable penetrance of the ID phenotype. Therefore, there is currently not enough evidence to classify as Green.Created: 23 Dec 2020, 12:02 p.m. | Last Modified: 23 Dec 2020, 12:02 p.m.
Panel Version: 3.678
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Difficult when novel genes are reported in large cohorts where multiple novel candidates are being put forward and additional phenotypic/segregation information is limited; however, note that three of the four studies are described as moderate-severe or severe ID cohorts.Created: 6 Feb 2020, 10:43 p.m. | Last Modified: 6 Feb 2020, 10:43 p.m.
Panel Version: 3.0
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Phenotype perhaps too mild in reported cases. Further evidence would assist.Created: 8 Mar 2018, 1:35 p.m.
Comment on mode of pathogenicity: Single pathogenic GOF variant identified p.(A636T)Created: 6 Mar 2018, 6:15 p.m.
Not associated with phenotype in OMIM or G2P. Single gof variant reported in at least 6 unrelated cases all with autistic syndrome disorder and 4 with features of ID. The variants appear to be de novo in two cases. Supporting functional studies provided in PMID 28628100.
Reported as De novo variant in severe ID case (de Ligt 2012 PMID 23033978) and as a candidate ID gene (Grozeva 2015 PMID 26350204, Gilessen 2014 PMID 24896178)
Created: 6 Mar 2018, 5:24 p.m.
Tag watchlist_moi tag was added to gene: GRIA1.
Tag Autism Spectrum Disorder was removed from gene: GRIA1. Tag Q2_23_promote_green was removed from gene: GRIA1.
Source NHS GMS was added to GRIA1. Source Expert Review Green was added to GRIA1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: gria1 has been classified as Amber List (Moderate Evidence).
Gene: gria1 has been classified as Amber List (Moderate Evidence).
Gene: gria1 has been classified as Amber List (Moderate Evidence).
Gene: gria1 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Mode of inheritance for gene: GRIA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: GRIA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: GRIA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tag watchlist was removed from gene: GRIA1. Tag Q2_23_promote_green tag was added to gene: GRIA1.
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Publications for gene: GRIA1 were set to 28628100; 23033978; 26350204; 24896178; 35675825
Mode of inheritance for gene: GRIA1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Publications for gene: GRIA1 were set to 28628100; 23033978; 26350204; 24896178; 35675825
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Phenotypes for gene: GRIA1 were changed from Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931 to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Phenotypes for gene: GRIA1 were changed from Intellectual disability to Intellectual developmental disorder, autosomal dominant 67, OMIM:619927; ?Intellectual developmental disorder, autosomal recessive 76, OMIM:619931
Publications for gene: GRIA1 were set to 28628100; 23033978; 26350204; 24896178; 35675825
Publications for gene: GRIA1 were set to 28628100; 23033978; 26350204; 24896178; 35675825
Publications for gene: GRIA1 were set to 28628100; 23033978; 26350204; 24896178; 35675825
Publications for gene: GRIA1 were set to 28628100; 23033978; 26350204; 24896178; 35675825
Publications for gene: GRIA1 were set to 28628100; 23033978; 26350204; 24896178
Gene: gria1 has been classified as Amber List (Moderate Evidence).
Phenotypes for GRIA1 were set to Intellectual disability
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.
Mode of pathogenicity for GRIA1 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Expert Review Amber was added to GRIA1. Panel: Intellectual disability Model of inheritance for gene GRIA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene GRIA1 was set to ['28628100', '23033978', '26350204', '24896178']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
GRIA1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
GRIA1 was created by ellenmcdonagh