GRM1

Chr 6ADAR

glutamate metabotropic receptor 1

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

NCBI Gene: 2911 ENSG00000152822 UniProt: Q13255 OMIM: 604473

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 OMIM 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 OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.412 OMIM phenotypes

Clinical Summary— GRM1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 226 VUS of 446 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GRM1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGRM1-related congenital cerebellar ataxiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7327th %ile

GOF

0.79top 25%

LOF

0.3452th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNHere, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-neg1

GOFIn vitro functional expression studies in HEK293FT cells showed that the mutation did not affect mGluR1 clustering at the plasma membrane, but that it resulted in increased transcriptional activation and excessive mGluR1 signaling, consistent with a gain-of-function effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 28886343 ↗

ClinVar Variant Classifications

446 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic6

VUS226

Likely Benign142

Benign48

Conflicting9

Pathogenic

Likely Pathogenic

226

VUS

142

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	3	0	0	9
Likely Pathogenic	5	1	0	0	6
VUS	3	208	7	8	226
Likely Benign	0	13	24	105	142
Benign	0	1	31	16	48
Conflicting	—				9
Total	14	226	62	129	440

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap GRM1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →