GRM1

Chr 6ADAR

glutamate metabotropic receptor 1

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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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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 OE0.24 (0.15–0.41)

0≤0.351.4

Missense OE0.72 (0.67–0.77)

0≤0.61.4

Synonymous OE1.22

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

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-negPMID:28886343

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.PMID:28886343

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.