GRM7

protein-coding

glutamate metabotropic receptor 7, the group of Glutamate metabotropic receptors|Protein phosphatase 1 regulatory subunits

Gene summary

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]

MANE transcript

NM_000844.4

Inheritance

ClinVar variants

P:12U:154B:118

Top phenotype

Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr3:6,770,001-7,741,533

External References & Databases

Ensembl (ENSG00000196277)

Transcript & Mutation Effects

hg38 • Region Span ~971.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030063

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030063

Submitter: G2P

neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030063

Submitter: PanelApp Australia

neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalitiesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030063

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalitiesAR

Manifestation: Craniofacial; Endocrine; Neurologic

Intervention: General

Rationale: Among other findings, individuals have been described with endocrine abnormalities, including panhypopituitarism, hypothyroidism, and growth hormone deficiency, and awareness may allow early diagnosis and management of these sequelae

Refs: 27435318; 28097321; 32286009

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GRM7 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 208

Inborn genetic diseasesTotal: 98

Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalitiesTotal: 19

GRM7-related disorderTotal: 6

Global developmental delayTotal: 4

not specifiedTotal: 4

Brain atrophyTotal: 3

HypotoniaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000844.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	98 clinvar	11 clinvar	111
missense	3 clinvar	4 clinvar	151 clinvar	8 clinvar	1 clinvar	167
nonsense	4 clinvar	1 clinvar	1 clinvar			6
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	7	5	154	106	12	284

Highest pathogenic variant AF is 0.000019827747

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000844.4	RefSeq	NP_000835.1	10	MANE Select
ENST00000357716.9	Ensembl	ENSP00000350348.4	10	MANE Select
NM_181874.3	RefSeq	NP_870989.1	10	Standard
ENST00000389335.7	Ensembl	ENSP00000373986.3	10	Standard

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

behavioral fear response
G protein-coupled receptor signaling pathway
adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway
G protein-coupled glutamate receptor signaling pathway
chemical synaptic transmission

Molecular Function

group III metabotropic glutamate receptor activity
calcium channel regulator activity
glutamate receptor activity
adenylate cyclase inhibitor activity
serine binding

Cellular Component

plasma membrane
integral component of plasma membrane
cell cortex
integral component of membrane
axon

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357716
Coding exons: 10
Length: 971528
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 125748
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.05	402	536	0.750	0.0000305	5992
Missense (PolyPhen)		151	259.66	0.58154		2822
Synonymous	-1.39	240	214	1.12	0.0000131	1809
Loss of Function	5.07	4	37.6	0.107	0.00000193	428

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00014	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000054	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

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. {ECO:0000269|PubMed:9473604}.;

Recessive Scores

pRec: 0.0937

Intolerance Scores

LoFtool: 0.00124
RVIS EVS: -1.62
RVIS percentile EVS: 2.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.341

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium