GRM7

Chr 3AR

glutamate metabotropic receptor 7

Also known as: GLUR7, GPRC1G, MGLU7, MGLUR7, NEDSHBA, PPP1R87

NCBI Gene: 2917 ENSG00000196277 UniProt: Q14831 OMIM: 604101

This protein is a Group III metabotropic glutamate receptor that inhibits adenylate cyclase and regulates axon outgrowth through MAPK-cAMP-PKA signaling during neuronal development. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with seizures, hypotonia, and brain abnormalities. The gene is highly constrained against loss-of-function variation (pLI = 1.0, LOEUF = 0.24), indicating that haploinsufficiency is likely not tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

L-glutamate is the major excitatory neurotransmitter in the central nervous system, and it 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 metabotropic glutamate receptors are a family of G protein-coupled receptors that have been divided into three groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5, and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3, while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with seizures, hypotonia, and brain abnormalitiesMIM #618922

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Neurodevelopmental disorder with seizures, hypotonia, and brain abnormalities; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.24

LOEUF· LoF intol.

—

Mechanism

📖

GeneReview available — GRM7

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.999

Z-score 5.07

OE 0.11 (0.05–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.05Z-score

OE missense 0.75 (0.69–0.81)

402 obs / 535.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.11 (0.05–0.24)

0≤0.351.4

Missense OE?0.75 (0.69–0.81)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 4 / 37.6Missense obs/exp: 402 / 535.8Syn Z: -1.39

Background carrier burden — how many people carry a rare variant somewhere in GRM7?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 87

1,135 rare PASS variants

Rare truncating (LoF)

1 in 1,100

97 rare PASS variants

Rare synonymous (reference)

1 in 64

534 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GRM7. 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 96	1 in 1,500
South Asian	~43k	1 in 76	1 in 520
Remaining (unassigned)	~30k	1 in 81	1 in 2,600
European (Finnish)	~27k	1 in 140	1 in 3,800
Admixed American	~22k	1 in 87	1 in 580
African / African American	~21k	1 in 84	1 in 720
East Asian	~20k	1 in 53	1 in 510
Ashkenazi Jewish	~13k	1 in 180	1 in 930
Middle Eastern	~2,884	1 in 110	≈ 1 in 2,800

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): 9 of 10 coding exons well covered in gnomAD exomes; exon 10 marginal. Genomes: all 10.? see exons ↓