GeneBe

GRM6

protein-coding

glutamate metabotropic receptor 6, the group of Glutamate metabotropic receptors

Gene summary

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 metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 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. Mutations in this gene result in congenital stationary night blindness type 1B. [provided by RefSeq, May 2018]

MANE transcript

NM_000843.4

Inheritance

AR

ClinVar variants

P:80U:459B:301

Top phenotype

Night blindness, congenital stationary, type 1B

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr5:178,977,587-178,996,206

External References & Databases

Ensembl (ENSG00000113262)NCBI Gene (2916)OMIM (604096)HGNC:4598GenCCUniProt (O15303)AlphaFoldClinVar (GRM6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~18.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital stationary night blindness 1BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009758

Submitter: G2P

congenital stationary night blindness 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009758

Submitter: PanelApp Australia

GRM6-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800397

Submitter: ClinGen

*GRM6* was first reported in relation to autosomal recessive congenital stationary night blindness in 2005 (Dryja et al., PMID: 15781871). Congenital stationary night blindness is a clinical and genetically heterogeneous group of nonprogressive retinal disorder that can be characterized by impaired night vision, decreased visual acuity, nystagmus, myopia, and strabismus (OMIM#301500). 11 variants (variant type, e.g. missense, nonsense, frameshift) that have been reported in 5 probands in 2 publications (PMIDs: 15781871, 16249515, 26628857) that are included in this curation. Segregation data was found in 2 families (PMID:16249515, 26628857). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism and inheritance pattern (autosomal recessive) to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease. Therefore, cases caused by inherited *GRM6* variants have been lumped into a single disease entity, referred to as *GRM6*-related retinopathy (MONDO:0800397). This gene-disease association is also supported by Grm6-deficient mouse model (PMID: 7889569). In the mammalian eye, the ON-centre and OFF-centre retinal ganglion cells form two major pathways projecting to central visual structures from the retina. Electroretinogram analysis and recordings from the superior colliculus indicated that the homozygous mutant mice showed a loss of ON responses but unchanged OFF responses to light, demonstrating that *GRM6* is essential in synaptic transmission to the ON bipolar cell (PMID: 7889569). In another *in vitro* experiment, mutant transfected HEK293T cells demonstrated defects in protein localization when compared to wildtype (PMID:17405131). Preliminary evidence demonstrated that *GRM6* gene therapy could restore vision in mice with retinal degeneration (PMID:32258214). In summary, *GRM6* is definitively associated with *GRM6*-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on September 1st, 2022 (SOP Version 9).

congenital stationary night blindness 1BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009758

Submitter: Ambry Genetics

congenital stationary night blindness 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009758

Submitter: Labcorp Genetics (formerly Invitae)

congenital stationary night blindness 1BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009758

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Night blindness, congenital stationary, type 1BAR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 11874764; 15781871; 16249515; 16622103; 22008250Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRM6 variants in ClinVar

12 Conditions Cataloged
not providedTotal: 844
Inborn genetic diseasesTotal: 156
not specifiedTotal: 155
GRM6-related disorderTotal: 48
Congenital stationary night blindness 1BTotal: 41
GRM6-related disordersTotal: 24
Retinal dystrophyTotal: 10
Congenital stationary night blindnessTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000843.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
253
clinvar
5
clinvar
 260
missense
1
clinvar
11
clinvar
455
clinvar
39
clinvar
4
clinvar
 510
nonsense
15
clinvar
9
clinvar
1
clinvar
 25
start loss
1
clinvar
 1
frameshift
21
clinvar
12
clinvar
1
clinvar
 34
splice donor/acceptor (+/-2bp)
2
clinvar
8
clinvar
 10
Total39414592929840

Highest pathogenic variant AF is 0.00021190799

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000843.4RefSeqNP_000834.210MANE Select
ENST00000517717.3EnsemblENSP00000430767.110MANE Select
ENST00000231188.9EnsemblENSP00000231188.510Standard
ENST00000650031.1EnsemblENSP00000497110.110Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
grm6bDanio rerio

Structure: retina

Quality: decreased functionality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Glutamatergic synapse - Homo sapiens (human)
  • Phospholipase D signaling pathway - Homo sapiens (human)
  • Neuroactive ligand-receptor interaction - Homo sapiens (human)
  • GPCRs, Class C Metabotropic glutamate, pheromone
  • Signaling by GPCR

Biological Process

  • G protein-coupled receptor signaling pathway
  • adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway
  • G protein-coupled glutamate receptor signaling pathway
  • detection of visible light
  • detection of light stimulus involved in visual perception

Molecular Function

  • G protein-coupled receptor activity
  • protein binding
  • glutamate receptor activity
  • protein homodimerization activity

Cellular Component

  • Golgi membrane
  • endoplasmic reticulum membrane
  • plasma membrane
  • integral component of plasma membrane
  • dendrite

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000231188
Coding exons
10
Length
17880
Individuals with no LoFs
125557
Homozygous LoFs
1
Heterozygous LoFs
190
Defined
125748
p
0.000760
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.5125345021.060.00003405512
Missense (PolyPhen)212203.271.04292288
Synonymous-0.8872362191.080.00001611885
Loss of Function0.7782832.80.8530.00000173332

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000490.00049rare
Latino/Admixed American0.000520.00049rare
Ashkenazi Jewish0.000300.00030rare
East Asian0.000440.00044rare
Finnish0.00130.0013notable
European (Non-Finnish)0.000690.00069rare
South Asian0.00140.0014notable
Other0.000990.00098rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity (By similarity). Signaling stimulates TRPM1 channel activity and Ca(2+) uptake. Required for normal vision. {ECO:0000250, ECO:0000269|PubMed:23452348}.;

Intolerance Scores

LoFtool
0.0620
RVIS EVS
-1.32
RVIS percentile EVS
4.79

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Indispensability pred.
N
Indispensability score
0.105

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.