GRIA3
protein-codingglutamate ionotropic receptor AMPA type subunit 3, the group of Glutamate ionotropic receptor AMPA type subunits
Gene summary
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes composed of multiple subunits, arranged to form ligand-gated ion channels. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The subunit encoded by this gene belongs to a family of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive glutamate receptors, and is subject to RNA editing (AGA->GGA; R->G). Alternative splicing at this locus results in different isoforms, which may vary in their signal transduction properties. [provided by RefSeq, Jul 2008]
- GLUR3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~306.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0100148
Submitter: ClinGen
*GRIA3* is located on chromosome Xq25 and encodes a subunit of AMPA-type ionotropic glutamate receptors that mediate excitatory synaptic transmission in the central nervous system and are essential for most brain functions, including learning and memory. *GRIA3* was first reported in relation to X-linked complex neurodevelopmental disorder in 2007 (Wu et al., PMID: 17989220). Affected individuals exhibit global developmental delay, intellectual disability (mostly moderate or severe), seizures (including developmental and epileptic encephalopathy), limited or absent speech, hypotonia or hypertonia, movement disorders (including hyperekplexia, erratic non-epileptic myoclonus, and ataxia), behavioral abnormalities (including aggressive outbursts, and autism or autistic features) and variable dysmorphic features. Most of the reported variants are missense and concentrate on domains responsible for glutamate binding and channel gating. Pathogenic variants alter receptor function and show loss-of-function (LoF) or gain-of-function (GoF) properties on electrophysiological assays. LoF and GoF variants can cause disease in both sexes but affected males predominantly carry hemizygous LoF variants inherited from healthy mothers, whereas most affected females carry *de novo* heterozygous GoF variants (PMID: 35318360). Genotype-phenotype correlation analysis showed that GoF variants were associated with more severe outcomes: patients were younger at the time of seizure onset (median age: 1 month), and had hypertonia and movement disorders, including hyperekplexia. Patients with LoF variants were older at the time of seizure onset (median age: 16 months), and had hypotonia and sleeping disturbances (PMID: 35318360). Fifteen variants (12 missense, 1 nonsense, 1 frameshift and 1 partial gene duplication leading to decreased expression) that have been reported in 15 probands in 10 publications (PMIDs: 17568425, 17989220, 21376300, 24721225, 25644381, 26637798, 28708303, 29016847, 31406558, 35318360) are included in this curation. Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity of truncating variants is LoF, while missense variants can lead to LoF or GoF. LoF effects on receptor signaling function include decreased or complete loss of current response to glutamate, reduced agonist sensitivity, reduced activation ability, increased desensitization, and/or decreased AMPA receptor surface expression (PMIDs: 35318360, 37921875). In contrast, GoF effects include increased current amplitudes, agonist sensitivity, and activation, constitutive activity and/or reduced or blocked desensitization. This gene-disease relationship is also supported by biochemical function, functional studies and mouse models (PMIDs: 12848940, 16436610, 18312590, 22285418, 35697757, 37921875). The three other genes encoding AMPA-type ionotropic glutamate receptors subunits, *GRIA1*, *GRIA2*, and *GRIA4*, are also involved in neurodevelopmental disorders with overlapping features. In summary, there is definitive evidence supporting the relationship between *GRIA3* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel in 2017 and reevaluated in 2019. It was reevaluated again on August 19, 2026 (SOP Version 12). Although new cases and experimental evidence were added, the classification did not change.
Inheritance Pattern: XL
Disease ID:MONDO:0010402
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0018222
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010402
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010402
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010402
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GRIA3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_007325.5. 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 | 26 | 133 | 7 | 166 | ||
| missense | 12 | 18 | 299 | 30 | 1 | 360 |
| nonsense | 5 | 15 | 20 | |||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 2 | 4 | 1 | 10 | |
| splice donor/acceptor (+/-2bp) | 1 | 25 | 26 | |||
| Total | 15 | 26 | 370 | 163 | 9 | 583 |
Highest pathogenic variant AF is 0.000008957523
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_015564.5 | 15 | MANE Select | |
| Ensembl | ENSP00000478489.1 | 15 | MANE Select | |
| RefSeq | NP_000819.4 | 15 | MANE Plus Clinical | |
| RefSeq | NP_001243672.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gria3a | Danio rerio | Structure: whole organism Quality: dead abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Retrograde endocannabinoid signaling - Homo sapiens (human)
- Dopaminergic synapse - Homo sapiens (human)
- Glutamatergic synapse - Homo sapiens (human)
- Long-term depression - Homo sapiens (human)
- Nicotine addiction - Homo sapiens (human)
Biological Process
- glutamate receptor signaling pathway
- ion transmembrane transport
- ionotropic glutamate receptor signaling pathway
- regulation of postsynaptic membrane potential
Molecular Function
- amyloid-beta binding
- AMPA glutamate receptor activity
- transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential
Cellular Component
- plasma membrane
- cell junction
- endocytic vesicle membrane
- AMPA glutamate receptor complex
- postsynaptic membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000264357
- Coding exons
- 15
- Length
- 306761
- Individuals with no LoFs
- 125704
- Homozygous LoFs
- 2
- Heterozygous LoFs
- 3
- Defined
- 125709
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.23 | 130 | 354 | 0.368 | 0.0000270 | 5888 |
| Missense (PolyPhen) | 40 | 161.29 | 0.248 | 2707 | ||
| Synonymous | 0.302 | 131 | 135 | 0.967 | 0.0000112 | 1698 |
| Loss of Function | 4.97 | 2 | 32.6 | 0.0613 | 0.00000259 | 531 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000076 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00013 | 0.000099 | rare |
| East Asian | 0.000072 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000024 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L- glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. {ECO:0000269|PubMed:21172611}.;
- Disease
- DISEASE: Mental retardation, X-linked 94 (MRX94) [MIM:300699]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non- syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX94 patients have moderate mental retardation. Other variable features are macrocephaly, seizures, myoclonic jerks, autistic behavior, asthenic body habitus, distal muscle weakness and hyporeflexia. {ECO:0000269|PubMed:17989220}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.176
Intolerance Scores
- LoFtool
- 0.107
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 45.13
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.652
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |