GeneBe

GRIN1

protein-coding

glutamate ionotropic receptor NMDA type subunit 1, the group of Glutamate ionotropic receptor NMDA type subunits

Gene summary

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. Cell-specific factors are thought to control expression of different isoforms, possibly contributing to the functional diversity of the subunits. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

Previous symbols:
  • NMDAR1

MANE transcript

NM_007327.4

Inheritance

AD, AR

ClinVar variants

P:146U:360B:394

Top phenotype

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive; Developmental and epileptic encephalopathy 101

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr9:137,138,346-137,168,756

External References & Databases

Ensembl (ENSG00000176884)NCBI Gene (2902)OMIM (138249)HGNC:4584GenCCUniProt (Q05586)AlphaFoldClinVar (GRIN1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~30.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013655

Submitter: PanelApp Australia

neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013655

Submitter: G2P

GRIN1-related complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:1060123

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*GRIN1* was first reported in relation to autosomal recessive (AR) complex neurodevelopmental disorder in 2016 (Bosch et al., PMID: 26350515). Phenotypic features in individuals with biallelic *GRIN1* variants include intellectual disability, hypotonia, autism spectrum disorder, stereotypic movements, feeding difficulties and brain abnormalities. Seizures and early death have been reported in individuals with homozygous nonsense variants (PMID 27164704, 35393335). Of note, there have also been many reported cases of individuals with heterozygous missense variants in *GRIN1* and complex neurodevelopmental disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and molecular mechanism, with the AR presentation being primarily loss of function variants and the AD presentation being primarily missense variants. Therefore, the curations for AD and AR complex neurodevelopmental disorder have been split, and cases with AD *GRIN1* variants have been curated separately by the Epilepsy GCEP. Six homozygous variants reported in six probands in five publications are included in this curation (PMIDs: 34611970, 35393335, 28051072, 27164704, 26350515). The mechanism of pathogenicity appears to be loss of function (PMID: 27164704). This gene-disease relationship is also supported by mouse models (PMIDs: 19794189, 22726567). In summary, there is definitive evidence supporting the relationship between *GRIN1* and AR complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date April 4, 2023 (SOP Version 9).

neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013655

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy 101STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030727

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominantMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013655

Submitter: Ambry Genetics

neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0060629

Submitter: G2P

neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0060629

Submitter: Ambry Genetics

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

The relationship between GRIN1 and autosomal dominant (AD) complex neurodevelopmental disorder was evaluated using the ClinGen Clinical Validity Framework as of 11/19/2018. Variants in GRIN1 were first reported in humans with this disease as early as 2011 (Hamdan et al., PMID: 21376300). At least 16 variants (e.g. missense, in-frame indel, in-frame duplications) have been reported in humans (PMID: 21376300, 27164704, 25864721, 28228639). Evidence supporting this gene-disease relationship includes de novo case-level data, and experimental data. Of note, there are animal models supporting that loss of function of the GRIN1 protein results in complex neurodevelopmental disorder, but these models are full knockouts that are used to support the gene's association with autosomal recessive disease. Variants in this gene have been reported in at least 33 probands in 4 publications (PMID: 21376300, 27164704, 25864721, 28228639). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is predicted to be dominant negative/haploinsufficiency (PMID: 27164704). Of note, this gene has also been implicated in causing disease in an autosomal recessive pattern. This will be assessed separately. This gene-disease association is supported by in vitro functional assays showing that the de novo variants may cause a dominant negative impact resulting in a loss of function of the transmembrane domain (PMID: 27164704). In summary, GRIN1 is definitively associated with AD complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant; Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive; Developmental and epileptic encephalopathy 101AD/AR

Manifestation: Craniofacial; 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

Refs: 21376300; 27164704; 28051072; 34611970Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRIN1 variants in ClinVar

20 Conditions Cataloged
Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominantTotal: 1019
not providedTotal: 304
Inborn genetic diseasesTotal: 106
not specifiedTotal: 84
GRIN1-related disorderTotal: 18
Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessiveTotal: 18
Intellectual disabilityTotal: 12
Developmental and epileptic encephalopathy 101Total: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007327.4. 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.

EffectPLPVUSLBBSum
synonymous
15
clinvar
312
clinvar
11
clinvar
 338
missense
37
clinvar
77
clinvar
338
clinvar
59
clinvar
6
clinvar
 517
nonsense
5
clinvar
2
clinvar
1
clinvar
1
clinvar
 9
start loss
3
clinvar
 3
frameshift
10
clinvar
4
clinvar
5
clinvar
 19
splice donor/acceptor (+/-2bp)
1
clinvar
10
clinvar
1
clinvar
2
clinvar
 14
Total539336037717900

Highest pathogenic variant AF is 0.000006843868

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_007327.4RefSeqNP_015566.120MANE Select
ENST00000371561.8EnsemblENSP00000360616.320MANE Select
NM_000832.7RefSeqNP_000823.419Standard
NM_001185090.2RefSeqNP_001172019.121Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Long-term potentiation - Homo sapiens (human)
  • Glutamatergic synapse - Homo sapiens (human)
  • Alzheimer,s disease - Homo sapiens (human)
  • Amyotrophic lateral sclerosis (ALS) - Homo sapiens (human)
  • Huntington,s disease - Homo sapiens (human)

Biological Process

  • MAPK cascade
  • conditioned taste aversion
  • suckling behavior
  • response to amphetamine
  • cation transport

Molecular Function

  • amyloid-beta binding
  • NMDA glutamate receptor activity
  • Ras guanyl-nucleotide exchange factor activity
  • signaling receptor binding
  • calcium channel activity

Cellular Component

  • cytoplasm
  • endoplasmic reticulum
  • plasma membrane
  • integral component of plasma membrane
  • synaptic vesicle

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000371553
Coding exons
21
Length
30366
Individuals with no LoFs
125713
Homozygous LoFs
0
Heterozygous LoFs
21
Defined
125734
p
0.0000835
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense6.221635870.2780.00003436179
Missense (PolyPhen)37231.40.15992358
Synonymous0.6712392530.9460.00001581864
Loss of Function5.25846.80.1710.00000223505

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000130.00012rare
Latino/Admixed American0.0000880.000087rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.000120.00011rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:7685113, PubMed:28126851, PubMed:26919761, PubMed:26875626, PubMed:28105280). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:26919761). {ECO:0000269|PubMed:26875626, ECO:0000269|PubMed:26919761, ECO:0000269|PubMed:28105280, ECO:0000269|PubMed:28126851, ECO:0000269|PubMed:7685113}.;
Disease
DISEASE: Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (NDHMSD) [MIM:614254]: An autosomal dominant neurodevelopmental disorder characterized by severe mental retardation and developmental delay, absent speech, muscular hypotonia, dyskinesia, and hyperkinetic movements. Cortical blindness, cerebral atrophy, and seizures are present in some patients. {ECO:0000269|PubMed:21376300, ECO:0000269|PubMed:25167861, ECO:0000269|PubMed:25864721, ECO:0000269|PubMed:27164704, ECO:0000269|PubMed:28095420, ECO:0000269|PubMed:28228639, ECO:0000269|PubMed:28389307}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (NDHMSR) [MIM:617820]: An autosomal recessive neurodevelopmental disorder characterized by severe mental retardation and psychomotor developmental delay, involuntary and stereotypic movements, spasticity, and inability to walk without support. Intractable seizures manifest in some patients. {ECO:0000269|PubMed:27164704, ECO:0000269|PubMed:28051072}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.238

Intolerance Scores

LoFtool
0.0986
RVIS EVS
-1.11
RVIS percentile EVS
6.72

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.810

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumLowMedium
Primary ImmunodeficiencyMediumLowMedium
CancerMediumMediumMedium
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