Human Gene Module / Chromosome 9 / GRIN1

GRIN1Glutamate receptor, ionotropic, N-methyl D-aspartate 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
1 / 18
Rare Variants / Common Variants
40 / 0
Aliases
GRIN1, RP11-350O14.1,  GluN1,  MRD8,  NMDA1,  NMDAR1,  NR1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
9q34.3
Associated Disorders
DD/NDD, ID, ASD
Relevance to Autism

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013).

Molecular Function

The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits play a key role in the plasticity of synapses, which is believed to underlie memory and learning.

Reports related to GRIN1 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction Gandal MJ , et al. (2012) No -
2 Recent Recommendation Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes Saunders JA , et al. (2013) No -
3 Support De novo mutations in epileptic encephalopathies Epi4K Consortium , et al. (2013) No -
4 Recent Recommendation Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism Moy SS , et al. (2013) No -
5 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing Redin C , et al. (2014) No -
6 Recent Recommendation Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy Lemke JR , et al. (2016) No ASD
7 Support Mutations in HECW2 are associated with intellectual disability and epilepsy Halvardson J , et al. (2016) No -
8 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
9 Support Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy Rossi M , et al. (2017) No Stereotypic movements of the midline, hypotonia, a
10 Support Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology Ogden KK , et al. (2017) No -
11 Support GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function Chen W , et al. (2017) No Hypotonia, stereotypic behavior
12 Support De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy Zehavi Y , et al. (2017) No Early onset encephalopathy, hypotonia
13 Support Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility Yu Y , et al. (2018) No -
14 Support De novo mutations in GRIN1 cause extensive bilateral polymicrogyria Fry AE , et al. (2018) No Autistic features
15 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders Jiao Q , et al. (2019) No DD, ID, autistic behavior
16 Support Abnormal circadian rhythm in patients with GRIN1-related developmental epileptic encephalopathy Scala M , et al. (2019) No Stereotypies
17 Support De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases Li J , et al. (2019) No -
18 Support Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1 Sengar AS , et al. (2019) Yes -
Rare Variants   (40)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1045G>A p.Ala349Thr missense_variant Unknown - - 29317596 Yu Y , et al. (2018)
c.1858G>C p.Asp620His missense_variant De novo NA - 28228639 Chen W , et al. (2017)
c.1652T>C p.Leu551Pro missense_variant De novo NA - 29365063 Fry AE , et al. (2018)
c.1658C>T p.Pro553Leu missense_variant De novo NA - 29365063 Fry AE , et al. (2018)
c.1940A>G p.Tyr647Cys missense_variant De novo NA - 29365063 Fry AE , et al. (2018)
c.1949A>T p.Asn650Ile missense_variant De novo NA - 29365063 Fry AE , et al. (2018)
c.1958C>G p.Ala653Gly missense_variant De novo NA - 29365063 Fry AE , et al. (2018)
c.1975C>T p.Arg659Trp missense_variant De novo NA - 29365063 Fry AE , et al. (2018)
c.2021A>T p.Asn674Ile missense_variant De novo NA - 29365063 Fry AE , et al. (2018)
c.2365G>A p.Asp789Asn missense_variant De novo NA - 29365063 Fry AE , et al. (2018)
c.2381G>A p.Arg794Gln missense_variant De novo NA - 29365063 Fry AE , et al. (2018)
c.2530C>T p.Arg844Cys missense_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.1923G>A p.Gly641= missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.2479G>A p.Ala827Thr missense_variant Unknown - - 27164704 Lemke JR , et al. (2016)
c.1654A>C p.Lys552Gln missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.1656C>A p.Asp552Glu missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.1670C>G p.Pro557Arg missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.1795G>C p.Asp599His missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.1852G>C p.Glu618Gln missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.1933G>T p.Ala645Ser missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.1940A>C p.Tyr647Ser missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.1950C>G p.Asn650Lys missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.1984G>A p.Glu662Lys missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.2416G>A p.Ala806Thr missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.2443G>A p.Gly815Arg missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.2444G>T p.Arg815Leu missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.2449T>C p.Phe817Leu missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.2530C>T p.Arg844Cys missense_variant De novo NA - 27164704 Lemke JR , et al. (2016)
c.2063C>A p.Ser688Tyr missense_variant De novo NA - 28389307 Zehavi Y , et al. (2017)
c.2479G>A p.Ala827Thr missense_variant De novo NA - 28389307 Zehavi Y , et al. (2017)
c.2272G>A p.Glu758Lys missense_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.1858G>A p.Asp620Asn missense_variant De novo NA Simplex 28228639 Chen W , et al. (2017)
c.1733C>G p.Pro578Arg missense_variant De novo NA Simplex 25167861 Redin C , et al. (2014)
c.2443G>A p.Gly815Arg missense_variant De novo NA Simplex 31176596 Scala M , et al. (2019)
c.2443G>T p.Gly815Trp missense_variant De novo NA Simplex 31176596 Scala M , et al. (2019)
c.1616_1618dup p.Thr539dup inframe_insertion De novo NA - 27164704 Lemke JR , et al. (2016)
c.1191A>C p.Arg397Ser missense_variant De novo NA Simplex 27334371 Halvardson J , et al. (2016)
c.1666C>T p.Gln556Ter stop_gained Familial Both parents Multiplex 27164704 Lemke JR , et al. (2016)
c.679G>C p.Ala227Pro missense_variant Familial Both parents Multiplex 28051072 Rossi M , et al. (2017)
c.649C>T p.Gln217Ter missense_variant Familial Both parents Multiplex 27164704 Lemke JR , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254). 7 of 28 individuals with GRIN1 variants in Lemke et al., 2016 had ASD in addition to intellectual disability with or without epilepsy; this included a homozygous partial loss-of-function GRIN1 missense variant in two siblings with ASD and ID from a consanguineous family, as well as two de novo loss-of-function missense variants in patients with ASD and severe ID.

Score Delta: Score remained at 3

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.

1/1/2020
3
icon
3

Score remained at 3

Description

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254). 7 of 28 individuals with GRIN1 variants in Lemke et al., 2016 had ASD in addition to intellectual disability with or without epilepsy; this included a homozygous partial loss-of-function GRIN1 missense variant in two siblings with ASD and ID from a consanguineous family, as well as two de novo loss-of-function missense variants in patients with ASD and severe ID.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254). 7 of 28 individuals with GRIN1 variants in Lemke et al., 2016 had ASD in addition to intellectual disability with or without epilepsy; this included a homozygous partial loss-of-function GRIN1 missense variant in two siblings with ASD and ID from a consanguineous family, as well as two de novo loss-of-function missense variants in patients with ASD and severe ID.

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254). 7 of 28 individuals with GRIN1 variants in Lemke et al., 2016 had ASD in addition to intellectual disability with or without epilepsy; this included a homozygous partial loss-of-function GRIN1 missense variant in two siblings with ASD and ID from a consanguineous family, as well as two de novo loss-of-function missense variants in patients with ASD and severe ID.

4/1/2019
3
icon
3

Decreased from 3 to 3

Description

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254). 7 of 28 individuals with GRIN1 variants in Lemke et al., 2016 had ASD in addition to intellectual disability with or without epilepsy; this included a homozygous partial loss-of-function GRIN1 missense variant in two siblings with ASD and ID from a consanguineous family, as well as two de novo loss-of-function missense variants in patients with ASD and severe ID.

4/1/2017
3
icon
3

Decreased from 3 to 3

Description

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254). 7 of 28 individuals with GRIN1 variants in Lemke et al., 2016 had ASD in addition to intellectual disability with or without epilepsy; this included a homozygous partial loss-of-function GRIN1 missense variant in two siblings with ASD and ID from a consanguineous family, as well as two de novo loss-of-function missense variants in patients with ASD and severe ID.

1/1/2017
3
icon
3

Decreased from 3 to 3

Description

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254). 7 of 28 individuals with GRIN1 variants in Lemke et al., 2016 had ASD in addition to intellectual disability with or without epilepsy; this included a homozygous partial loss-of-function GRIN1 missense variant in two siblings with ASD and ID from a consanguineous family, as well as two de novo loss-of-function missense variants in patients with ASD and severe ID.

7/1/2016
3
icon
3

Decreased from 3 to 3

Description

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254). 7 of 28 individuals with GRIN1 variants in Lemke et al., 2016 had ASD in addition to intellectual disability with or without epilepsy; this included a homozygous partial loss-of-function GRIN1 missense variant in two siblings with ASD and ID from a consanguineous family, as well as two de novo loss-of-function missense variants in patients with ASD and severe ID.

4/1/2016
5
icon
3

Decreased from 5 to 3

Description

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254). 7 of 28 individuals with GRIN1 variants in Lemke et al., 2016 had ASD in addition to intellectual disability with or without epilepsy; this included a homozygous partial loss-of-function GRIN1 missense variant in two siblings with ASD and ID from a consanguineous family, as well as two de novo loss-of-function missense variants in patients with ASD and severe ID.

7/1/2015
icon
5

Increased from to 5

Description

Decreased social interaction in GRIN1-knockout mice was observed in two separate studies (Gandal et al., 2012; Saunders et al., 2013). Mutations in GRIN1 are associated with an autosomal dominant form with intellectual disability (MRD8; OMIM 614254).

Krishnan Probability Score

Score 0.61251149887656

Ranking 167/25841 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.
ExAC Score

Score 0.97270894606804

Ranking 2310/18225 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
Sanders TADA Score

Score 0.9446230042452

Ranking 16148/18665 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).
Zhang D Score

Score 0.38612792655463

Ranking 1609/20870 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.
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