GRIN1

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

Basic information

Region (hg38): 9:137138345-137168756

Previous symbols: [ "NMDAR1" ]

Links

ENSG00000176884 ∙ NCBI:2902 ∙ OMIM:138249 ∙ HGNC:4584 ∙ Uniprot:Q05586 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, autosomal dominant 8 (Moderate), mode of inheritance: AD
• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (Moderate), mode of inheritance: AR
• autosomal dominant non-syndromic intellectual disability (Supportive), mode of inheritance: AD
• neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (Definitive), mode of inheritance: AR
• intellectual disability, autosomal dominant 8 (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy 101 (Strong), mode of inheritance: AR
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AR
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
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	AD/AR	General	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	Craniofacial; Neurologic	21376300; 27164704; 28051072; 34611970

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GRIN1 gene.

• Intellectual disability, autosomal dominant 8 (683 variants)
• not provided (246 variants)
• not specified (83 variants)
• Inborn genetic diseases (77 variants)
• Intellectual disability (9 variants)
• Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (8 variants)
• GRIN1-related condition (7 variants)
• See cases (4 variants)
• Developmental and epileptic encephalopathy 101 (2 variants)
• Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive;Intellectual disability, autosomal dominant 8 (2 variants)
• NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS WITH OR WITHOUT SEIZURES, AUTOSOMAL RECESSIVE (2 variants)
• GRIN1-Related Disorder (2 variants)
• Neurodevelopmental disorder (1 variants)
• Neurodevelopmental delay (1 variants)
• NEURODEVELOPMENTAL DISORDER WITH HYPERKINETIC MOVEMENTS AND WITH OR WITHOUT SEIZURES, AUTOSOMAL DOMINANT (1 variants)
• Seizure (1 variants)
• Developmental and epileptic encephalopathy 101;Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive;Intellectual disability, autosomal dominant 8 (1 variants)
• Intellectual disability, autosomal dominant 8;Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive;Developmental and epileptic encephalopathy 101 (1 variants)
• Hemimegalencephaly (1 variants)
• Intellectual disability, autosomal dominant 8;Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (1 variants)
• Autism spectrum disorder (1 variants)
• Autism (1 variants)
• Intellectual disability, autosomal dominant 8;Developmental and epileptic encephalopathy 101;Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (1 variants)
• Febrile seizure (within the age range of 3 months to 6 years);Autistic behavior;Global developmental delay;Expressive language delay;Macrocephaly (1 variants)
• Developmental and epileptic encephalopathy, 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GRIN1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	210	10	230
missense	22	42	185	26	9	284
nonsense			5	1		6
start loss			1	1		2
frameshift	2		7			9
inframe indel	1		5	3		9
splice donor/acceptor (+/-2bp)		2	2	2		6
splice region			18	39	5	62
non coding			10	165	29	204
Total	25	44	225	408	48

Highest pathogenic variant AF is 0.00000657

Variants in GRIN1

This is a list of pathogenic ClinVar variants found in the GRIN1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-137139197-AGCC-A			Likely benign (Jun 28, 2018)
9-137139452-C-A		not specified	Benign (Oct 11, 2016)
9-137139458-G-A		not specified	Likely benign (Mar 07, 2016)
9-137139463-G-A		not specified	Likely benign (Dec 15, 2016)
9-137139471-C-T		not specified	Likely benign (Apr 03, 2017)
9-137139487-A-T		Intellectual disability, autosomal dominant 8	Likely benign (Jan 22, 2024)
9-137139488-T-C		Intellectual disability, autosomal dominant 8	Uncertain significance (May 06, 2022)
9-137139491-G-A			Uncertain significance (Feb 25, 2022)
9-137139495-C-T		Intellectual disability, autosomal dominant 8	Likely benign (Sep 29, 2023)
9-137139500-G-A		Inborn genetic diseases • Intellectual disability, autosomal dominant 8	Uncertain significance (Dec 08, 2023)
9-137139508-A-C		Intellectual disability • Intellectual disability, autosomal dominant 8	Benign/Likely benign (Feb 04, 2022)
9-137139509-C-T		Intellectual disability, autosomal dominant 8	Benign (Jul 19, 2022)
9-137139521-T-C		Intellectual disability, autosomal dominant 8	Uncertain significance (Aug 27, 2021)
9-137139522-G-C		Intellectual disability, autosomal dominant 8	Likely benign (Jan 03, 2018)
9-137139524-TCTC-T		Intellectual disability, autosomal dominant 8	Uncertain significance (Aug 26, 2020)
9-137139527-C-T		Intellectual disability, autosomal dominant 8	Uncertain significance (Aug 28, 2023)
9-137139546-C-G		Intellectual disability, autosomal dominant 8	Likely benign (Apr 07, 2023)
9-137139549-G-A		not specified • Intellectual disability, autosomal dominant 8	Likely benign (Sep 27, 2023)
9-137139552-C-T		Intellectual disability, autosomal dominant 8	Likely benign (Jan 10, 2024)
9-137139564-C-T		Intellectual disability, autosomal dominant 8	Likely benign (Jul 19, 2022)
9-137139566-T-G		Intellectual disability, autosomal dominant 8	Uncertain significance (Apr 04, 2024)
9-137139573-T-C		Inborn genetic diseases	Likely benign (Nov 02, 2017)
9-137139578-C-A		Intellectual disability, autosomal dominant 8	Uncertain significance (Jan 04, 2022)
9-137139589-A-G			Uncertain significance (Jan 15, 2019)
9-137139591-G-A		Intellectual disability, autosomal dominant 8	Likely benign (Jan 21, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GRIN1	protein_coding	protein_coding	ENST00000371553	21	30366

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.976	0.0237	125713	0	21	125734	0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.22	163	587	0.278	0.0000343	6179
Missense in Polyphen		37	231.4	0.1599		2358
Synonymous	0.671	239	253	0.946	0.0000158	1864
Loss of Function	5.25	8	46.8	0.171	0.00000223	505

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000218	0.000211
Ashkenazi Jewish	0.00	0.00
East Asian	0.000111	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000121	0.000114
Middle Eastern	0.000111	0.000109
South Asian	0.0000330	0.0000327
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Nicotine addiction - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Levomethadyl Acetate Action Action Pathway;Fluoxetine Action Pathway;Citalopram Action Pathway;Escitalopram Action Pathway;Imipramine Action Pathway;Desipramine Action Pathway;Levallorphan Action Pathway;Dimethylthiambutene Action Pathway;Ethylmorphine Action Pathway;Pentazocine Action Pathway;Naltrexone Action Pathway;Buprenorphine Action Pathway;Alvimopan Action Pathway;Naloxone Action Pathway;Dihydromorphine Action Pathway;Methadone Metabolism Pathway;Nicotine Action Pathway;Nalbuphine Action Pathway;Ketobemidone Action Pathway;Lidocaine (Local Anaesthetic) Action Pathway;Mepivacaine Action Pathway;Chloroprocaine Action Pathway;Cocaine Action Pathway;Dibucaine Action Pathway;Levobupivacaine Action Pathway;Benzocaine Action Pathway;Bupivacaine Action Pathway;Levorphanol Action Pathway;Propoxyphene Action Pathway;Tramadol Action Action Pathway;Diphenoxylate Action Pathway;Anileridine Action Pathway;Methadone Action Pathway;Oxycodone Action Pathway;Oxybuprocaine Action Pathway;Prilocaine Action Pathway;Procaine Action Pathway;Proparacaine Action Pathway;Ropivacaine Action Pathway;Codeine Action Pathway;Morphine Action Pathway;Heroin Action Pathway;Alfentanil Action Pathway;Oxymorphone Action Pathway;Hydrocodone Action Pathway;Hydromorphone Action Pathway;Sufentanil Action Pathway;Remifentanil Action Pathway;Fentanyl Action Pathway;Carfentanil Action Pathway;3-Methylthiofentanyl Action Pathway;Methadyl Acetate Action Pathway;Dezocine Action Pathway;Alzheimers Disease;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Spinal Cord Injury;Common Pathways Underlying Drug Addiction;MECP2 and Associated Rett Syndrome;Olfactory bulb development and olfactory learning;BDNF-TrkB Signaling;NO-cGMP-PKG mediated Neuroprotection;Splicing factor NOVA regulated synaptic proteins;Phosphodiesterases in neuronal function;Ras Signaling;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Developmental Biology;Signal Transduction;nitric oxide signaling pathway;GPCR Dopamine D1like receptor;EPH-Ephrin signaling;EPHB-mediated forward signaling;Neuronal System;Synaptic adhesion-like molecules;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Neurexins and neuroligins;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Axon guidance;Ras activation upon Ca2+ influx through NMDA receptor;CREB phosphorylation through the activation of Ras;Unblocking of NMDA receptor, glutamate binding and activation;CREB phosphorylation through the activation of CaMKII;Post NMDA receptor activation events;Activation of NMDA receptor and postsynaptic events;Protein-protein interactions at synapses (Consensus)

Recessive Scores

• pRec: 0.238

Intolerance Scores

• loftool: 0.0986
• rvis_EVS: -1.11
• rvis_percentile_EVS: 6.72

Haploinsufficiency Scores

• pHI: 0.298
• hipred: Y
• hipred_score: 0.850
• ghis: 0.729

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.810

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Low	Medium
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Grin1
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; reproductive system phenotype; growth/size/body region phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype

Gene ontology

• Biological process: MAPK cascade;conditioned taste aversion;suckling behavior;response to amphetamine;cation transport;brain development;respiratory gaseous exchange;long-term memory;adult locomotory behavior;olfactory learning;visual learning;positive regulation of calcium ion transport into cytosol;propylene metabolic process;sensory perception of pain;calcium-mediated signaling;pons maturation;cerebral cortex development;social behavior;ionotropic glutamate receptor signaling pathway;synaptic transmission, glutamatergic;regulation of membrane potential;positive regulation of apoptotic process;response to morphine;negative regulation of neuron apoptotic process;regulation of respiratory gaseous exchange;response to ethanol;positive regulation of transcription by RNA polymerase II;ephrin receptor signaling pathway;regulation of synaptic plasticity;regulation of long-term neuronal synaptic plasticity;regulation of dendrite morphogenesis;regulation of axonogenesis;protein heterotetramerization;regulation of synapse assembly;calcium ion homeostasis;excitatory postsynaptic potential;prepulse inhibition;male mating behavior;calcium ion transmembrane import into cytosol;excitatory chemical synaptic transmission;positive regulation of reactive oxygen species biosynthetic process;protein localization to postsynaptic membrane;cellular response to amyloid-beta;response to glycine;positive regulation of excitatory postsynaptic potential;positive regulation of cysteine-type endopeptidase activity
• Cellular component: cytoplasm;endoplasmic reticulum;plasma membrane;integral component of plasma membrane;synaptic vesicle;cell surface;postsynaptic density;NMDA selective glutamate receptor complex;cell junction;dendrite;neuron projection;synaptic cleft;terminal bouton;dendritic spine;synapse;postsynaptic membrane;excitatory synapse;synaptic membrane;glutamatergic synapse;integral component of postsynaptic density membrane
• Molecular function: amyloid-beta binding;NMDA glutamate receptor activity;Ras guanyl-nucleotide exchange factor activity;signaling receptor binding;calcium channel activity;calcium ion binding;protein binding;calmodulin binding;glycine binding;glutamate binding;glutamate-gated calcium ion channel activity;neurotransmitter binding;protein-containing complex binding;transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential