GRM1

protein-coding

glutamate metabotropic receptor 1, the group of Protein phosphatase 1 regulatory subunits|Glutamate metabotropic receptors

Gene summary

This gene encodes a metabotropic glutamate receptor that functions by activating phospholipase C. L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The canonical alpha isoform of the encoded protein is a disulfide-linked homodimer whose activity is mediated by a G-protein-coupled phosphatidylinositol-calcium second messenger system. This gene may be associated with many disease states, including schizophrenia, bipolar disorder, depression, and breast cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

MANE transcript

NM_001278064.2

Inheritance

AR, AD

ClinVar variants

P:16U:232B:146

Top phenotype

Spinocerebellar ataxia 44; Spinocerebellar ataxia, autosomal recessive 13

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr6:146,027,646-146,437,601

External References & Databases

Ensembl (ENSG00000152822)

Transcript & Mutation Effects

hg38 • Region Span ~410.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive spinocerebellar ataxia 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013905

Submitter: PanelApp Australia

autosomal recessive spinocerebellar ataxia 13SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013905

Submitter: Orphanet

spinocerebellar ataxia 44STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033479

Submitter: PanelApp Australia

autosomal recessive spinocerebellar ataxia 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013905

Submitter: G2P

spinocerebellar ataxia 44STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033479

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive spinocerebellar ataxia 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013905

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 44; Spinocerebellar ataxia, autosomal recessive 13AD/AR

Manifestation: 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: 22901947; 28886343

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRM1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 387

not specifiedTotal: 74

Spinocerebellar ataxia 44Total: 29

Autosomal recessive spinocerebellar ataxia 13Total: 29

Inborn genetic diseasesTotal: 20

GRM1-related disorderTotal: 17

Cerebellar ataxiaTotal: 2

GRM1-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001278064.2. 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			9 clinvar	122 clinvar	8 clinvar	139
missense	3 clinvar	1 clinvar	216 clinvar	16 clinvar		236
nonsense	2 clinvar	1 clinvar	1 clinvar			4
start loss						0
frameshift	3 clinvar	6 clinvar	4 clinvar			13
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	8	8	232	138	8	394

Highest pathogenic variant AF is 0.000006199874

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001278064.2	RefSeq	NP_001264993.1	8	MANE Select
ENST00000282753.6	Ensembl	ENSP00000282753.1	8	MANE Select
NM_001278065.2	RefSeq	NP_001264994.1	8	Standard
NM_001278066.1	RefSeq	NP_001264995.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Long-term potentiation - Homo sapiens (human)
Retrograde endocannabinoid signaling - Homo sapiens (human)
Glutamatergic synapse - Homo sapiens (human)
Long-term depression - Homo sapiens (human)
Gap junction - Homo sapiens (human)

Biological Process

activation of MAPKK activity
activation of MAPK activity
G protein-coupled receptor signaling pathway
G protein-coupled glutamate receptor signaling pathway
chemical synaptic transmission

Molecular Function

G protein-coupled receptor activity
protein binding
glutamate receptor activity
G protein-coupled neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration
G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential

Cellular Component

nucleus
plasma membrane
integral component of plasma membrane
dendrite
G protein-coupled receptor dimeric complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361719
Coding exons: 8
Length: 409953
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.58	475	662	0.718	0.0000394	7798
Missense (PolyPhen)		95	249.51	0.38074		2954
Synonymous	-2.83	333	273	1.22	0.0000175	2449
Loss of Function	4.47	10	40.9	0.245	0.00000232	479

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00021	0.00018	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling activates a phosphatidylinositol-calcium second messenger system. May participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum. {ECO:0000269|PubMed:24603153, ECO:0000269|PubMed:28886343, ECO:0000269|PubMed:7476890}.;
Disease: DISEASE: Spinocerebellar ataxia 44 (SCA44) [MIM:617691]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA44 is a slowly progressive, autosomal dominant form. {ECO:0000269|PubMed:28886343}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.186

Intolerance Scores

LoFtool: 0.0173
RVIS EVS: -0.15
RVIS percentile EVS: 42.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.775

Gene Damage Prediction

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