Human Gene Module / Chromosome 5 / GRIA1

GRIA1glutamate ionotropic receptor AMPA type subunit 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 12
Rare Variants / Common Variants
19 / 0
Aliases
GRIA1, GLUH1,  GLUR1,  GLURA,  GluA1,  HBGR1
Associated Syndromes
-
Chromosome Band
5q33.2
Associated Disorders
-
Relevance to Autism

A recurrent missense variant in the GRIA1 gene (p.Ala636Thr) was originally reported as de novo variants in patients with developmental delay/intellectual disability (De Ligt et al., 2012) and ASD (De Rubeis et al., 2014); the same variant was subsequently identified in three additional patients with a primary diagnosis of ASD (de novo in one case, unknown inheritance in the other two) in Geisheker et al., 2017. The p.Ala636Thr variant was not observed in over 60,000 individuals in ExAC (compared to being observed in 5 NDD cases, three of which were de novo; P=5.39E-03, one-tailed binomial test, genome-wide correction), and functional analysis of this variant using whole-cell voltage-clamp recordings of transfected HEK293 cells demonstrated a gain-of-function effect. Ismail et al., 2022 reported seven unrelated individuals with rare GRIA1 variants presenting with a neurodevelopmental syndrome characterized by intellectual disability, language impairment, and behavioral abnormalities (including autism spectrum disorder in three individuals); subsequent functional assessment of GRIA1 variants in this study showed that three of the four missense variants significantly disrupted receptor function, whereas a homozygous nonsense variant completely abolished expression of GluA1-containing AMPARs.

Molecular Function

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 with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GRIA1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Diagnostic exome sequencing in persons with severe intellectual disability de Ligt J , et al. (2012) No -
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Recent Recommendation Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
5 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
6 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Recent Recommendation - Ismail V et al. (2022) No ASD, ADHD
9 Support - Krgovic D et al. (2022) Yes DD, ID
10 Support - Levchenko O et al. (2022) No -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1913C>G p.Ser638Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1034G>A p.Arg345Gln missense_variant Unknown - - 35675825 Ismail V et al. (2022)
c.1906G>A p.Ala636Thr missense_variant De novo - - 35675825 Ismail V et al. (2022)
c.1496G>A p.Arg499Gln missense_variant De novo - - 35813072 Krgovic D et al. (2022)
c.1936G>A p.Ala646Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1994G>A p.Gly665Asp missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.1880T>C p.Ile627Thr missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.603C>A p.Asp201Glu missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1129C>T p.Arg377Ter stop_gained Familial Both parents - 35675825 Ismail V et al. (2022)
c.653G>A p.Arg218His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.329C>T p.Thr110Met missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1906G>A p.Ala636Thr missense_variant De novo - Simplex 23033978 de Ligt J , et al. (2012)
c.1906G>A p.Ala636Thr missense_variant Unknown - Unknown 35887114 Levchenko O et al. (2022)
c.1906G>A p.Ala636Thr missense_variant De novo - Simplex 28628100 Geisheker MR , et al. (2017)
c.772G>A p.Ala258Thr missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.1918G>T p.Val640Leu missense_variant Familial Paternal - 28628100 Geisheker MR , et al. (2017)
c.1906G>A p.Ala636Thr missense_variant Unknown Not maternal - 28628100 Geisheker MR , et al. (2017)
c.1906G>A p.Ala636Thr missense_variant Unknown Not maternal Simplex 28628100 Geisheker MR , et al. (2017)
c.1906G>A p.Ala636Thr missense_variant Unknown Not maternal Unknown 28628100 Geisheker MR , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A recurrent missense variant in the GRIA1 gene (p.Ala636Thr) was originally reported as de novo variants in patients with developmental delay/intellectual disability (De Ligt et al., 2012) and ASD (De Rubeis et al., 2014); the same variant was subsequently identified in three additional patients with a primary diagnosis of ASD (de novo in one case, unknown inheritance in the other two) in Geisheker et al., 2017. The p.Ala636Thr variant was not observed in over 60,000 individuals in ExAC (compared to being observed in 5 NDD cases, three of which were de novo; P=5.39E-03, one-tailed binomial test, genome-wide correction), and functional analysis of this variant using whole-cell voltage-clamp recordings of transfected HEK293 cells demonstrated a gain-of-function effect. Additional de novo damaging missense variants in this gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a proband with developmental delay (Geisheker et al., 2017).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
Description

A recurrent missense variant in the GRIA1 gene (p.Ala636Thr) was originally reported as de novo variants in patients with developmental delay/intellectual disability (De Ligt et al., 2012) and ASD (De Rubeis et al., 2014); the same variant was subsequently identified in three additional patients with a primary diagnosis of ASD (de novo in one case, unknown inheritance in the other two) in Geisheker et al., 2017. The p.Ala636Thr variant was not observed in over 60,000 individuals in ExAC (compared to being observed in 5 NDD cases, three of which were de novo; P=5.39E-03, one-tailed binomial test, genome-wide correction), and functional analysis of this variant using whole-cell voltage-clamp recordings of transfected HEK293 cells demonstrated a gain-of-function effect. Additional de novo damaging missense variants in this gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a proband with developmental delay (Geisheker et al., 2017).

Reports Added
[New Scoring Scheme]
7/1/2019
2
icon
2

Score remained at 2

Description

A recurrent missense variant in the GRIA1 gene (p.Ala636Thr) was originally reported as de novo variants in patients with developmental delay/intellectual disability (De Ligt et al., 2012) and ASD (De Rubeis et al., 2014); the same variant was subsequently identified in three additional patients with a primary diagnosis of ASD (de novo in one case, unknown inheritance in the other two) in Geisheker et al., 2017. The p.Ala636Thr variant was not observed in over 60,000 individuals in ExAC (compared to being observed in 5 NDD cases, three of which were de novo; P=5.39E-03, one-tailed binomial test, genome-wide correction), and functional analysis of this variant using whole-cell voltage-clamp recordings of transfected HEK293 cells demonstrated a gain-of-function effect. Additional de novo damaging missense variants in this gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a proband with developmental delay (Geisheker et al., 2017).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2018
2
icon
2

Score remained at 2

Description

A recurrent missense variant in the GRIA1 gene (p.Ala636Thr) was originally reported as de novo variants in patients with developmental delay/intellectual disability (De Ligt et al., 2012) and ASD (De Rubeis et al., 2014); the same variant was subsequently identified in three additional patients with a primary diagnosis of ASD (de novo in one case, unknown inheritance in the other two) in Geisheker et al., 2017. The p.Ala636Thr variant was not observed in over 60,000 individuals in ExAC (compared to being observed in 5 NDD cases, three of which were de novo; P=5.39E-03, one-tailed binomial test, genome-wide correction), and functional analysis of this variant using whole-cell voltage-clamp recordings of transfected HEK293 cells demonstrated a gain-of-function effect. Additional de novo damaging missense variants in this gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a proband with developmental delay (Geisheker et al., 2017).

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2017
icon
2

Increased from to 2

Description

A recurrent missense variant in the GRIA1 gene (p.Ala636Thr) was originally reported as de novo variants in patients with developmental delay/intellectual disability (De Ligt et al., 2012) and ASD (De Rubeis et al., 2014); the same variant was subsequently identified in three additional patients with a primary diagnosis of ASD (de novo in one case, unknown inheritance in the other two) in Geisheker et al., 2017. The p.Ala636Thr variant was not observed in over 60,000 individuals in ExAC (compared to being observed in 5 NDD cases, three of which were de novo; P=5.39E-03, one-tailed binomial test, genome-wide correction), and functional analysis of this variant using whole-cell voltage-clamp recordings of transfected HEK293 cells demonstrated a gain-of-function effect. Additional de novo damaging missense variants in this gene have been observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and a proband with developmental delay (Geisheker et al., 2017).

Krishnan Probability Score

Score 0.6152593707726

Ranking 122/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99943634084032

Ranking 957/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.21517291274344

Ranking 120/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.13841581675994

Ranking 5385/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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