GRM5

Chr 11

glutamate metabotropic receptor 5

Also known as: GPRC1E, MGLUR5, PPP1R86, mGlu5

NCBI Gene: 2915 ENSG00000168959 UniProt: P41594

The protein is a metabotropic glutamate receptor that activates phosphatidylinositol-calcium second messenger signaling and regulates synaptic plasticity and neural network activity. Mutations cause developmental and epileptic encephalopathy with an autosomal dominant inheritance pattern. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.25), indicating that functional copies are critical for normal development.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the G-protein coupled receptor 3 protein family. The encoded protein is a metabatropic glutamate receptor, whose signaling activates a phosphatidylinositol-calcium second messenger system. This protein may be involved in the regulation of neural network activity and synaptic plasticity. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. A pseudogene of this gene has been defined on chromosome 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

ResearchGenerating clinical summary…

Clinical highlights

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.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.25

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.25LOEUF

pLI 0.999

Z-score 5.24

OE 0.12 (0.06–0.25)

Highly constrained

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

Missense Constraint?

3.21Z-score

OE missense 0.65 (0.60–0.70)

425 obs / 656.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.25)

0≤0.351.4

Missense OE?0.65 (0.60–0.70)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 5 / 41.4Missense obs/exp: 425 / 656.2Syn Z: -2.25

Background carrier burden — how many people carry a rare variant somewhere in GRM5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 49

1,316 rare PASS variants

Rare truncating (LoF)

1 in 3,400

61 rare PASS variants

Rare synonymous (reference)

1 in 52

741 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GRM5. 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 64	1 in 4,200
South Asian	~43k	1 in 50	1 in 1,100
Remaining (unassigned)	~30k	1 in 46	1 in 2,900
European (Finnish)	~27k	1 in 110	≈ 1 in 27,000
Admixed American	~22k	1 in 55	1 in 2,500
African / African American	~21k	1 in 55	1 in 2,700
East Asian	~20k	1 in 71	1 in 3,600
Ashkenazi Jewish	~13k	1 in 110	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 71	≈ 1 in 1,900

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): 5 of 9 coding exons well covered in gnomAD exomes; exons 3, 6, 7, 9 marginal. Genomes: all 9.? see exons ↓