GRM1

Chr 6

glutamate metabotropic receptor 1

Also known as: GPRC1A, MGLU1, MGLUR1, PPP1R85, SCA44, SCAR13

NCBI Gene: 2911 ENSG00000152822 UniProt: Q13255

This protein is a G-protein coupled receptor for glutamate that activates phospholipase C and a phosphatidylinositol-calcium second messenger system, participating in synaptic plasticity including long-term potentiation in the hippocampus and long-term depression in the cerebellum. Mutations cause spinocerebellar ataxia 44 (autosomal dominant) and spinocerebellar ataxia, autosomal recessive 13, with pathogenicity predicted to result from gain-of-function mechanisms.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtSpinocerebellar ataxia, autosomal recessive, 13

UniProtSpinocerebellar ataxia 44

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.41

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — GRM1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.143

Z-score 4.47

OE 0.24 (0.15–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.58Z-score

OE missense 0.72 (0.67–0.77)

475 obs / 661.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.24 (0.15–0.41)

0≤0.351.4

Missense OE?0.72 (0.67–0.77)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 10 / 40.9Missense obs/exp: 475 / 661.9Syn Z: -2.83

Background carrier burden — how many people carry a rare variant somewhere in GRM1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

1,311 rare PASS variants

Rare truncating (LoF)

1 in 3,600

92 rare PASS variants

Rare synonymous (reference)

1 in 57

751 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GRM1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 67	1 in 3,400
South Asian	~43k	1 in 40	1 in 4,300
Remaining (unassigned)	~30k	1 in 60	1 in 3,800
European (Finnish)	~27k	1 in 190	1 in 2,100
Admixed American	~22k	1 in 71	1 in 1,700
African / African American	~21k	1 in 62	≈ 1 in 17,000
East Asian	~20k	1 in 67	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 250	none seen
Middle Eastern	~2,884	1 in 93	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓