GNRHR
protein-codinggonadotropin releasing hormone receptor, the group of Gonadotropin releasing hormone receptors
Gene summary
This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate. Following binding of gonadotropin-releasing hormone, the receptor associates with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). Defects in this gene are a cause of hypogonadotropic hypogonadism (HH). Alternative splicing results in multiple transcript variants encoding different isoforms. More than 18 transcription initiation sites in the 5' region and multiple polyA signals in the 3' region have been identified for this gene. [provided by RefSeq, Jul 2008]
- GRHR
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007794
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0007794
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018555
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0007794
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Genitourinary
Intervention: Endocrine
Rationale: In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required
Comments: Digenic inheritance (with FGFR1) has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GNRHR variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000406.3. 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 | 5 | 14 | 1 | 20 | ||
| missense | 12 | 21 | 59 | 2 | 94 | |
| nonsense | 3 | 2 | 2 | 7 | ||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 4 | 6 | |||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 18 | 29 | 67 | 16 | 1 | 131 |
Highest pathogenic variant AF is 0.00353684
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000397.1 | 3 | MANE Select | |
| Ensembl | ENSP00000226413.5 | 3 | MANE Select | |
| RefSeq | NP_001012781.1 | 3 | Standard | |
| Ensembl | ENSP00000397561.2 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- GnRH signaling pathway - Homo sapiens (human)
- Neuroactive ligand-receptor interaction - Homo sapiens (human)
- GPCRs, Other
- Peptide GPCRs
- Signaling by GPCR
Biological Process
- G protein-coupled receptor signaling pathway
- multicellular organism development
- cellular response to hormone stimulus
- cellular response to gonadotropin-releasing hormone
Molecular Function
- gonadotropin-releasing hormone receptor activity
Cellular Component
- plasma membrane
- integral component of plasma membrane
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000226413
- Coding exons
- 3
- Length
- 15033
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 125740
- p
- 0.0000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.301 | 155 | 166 | 0.934 | 0.00000821 | 2164 |
| Missense (PolyPhen) | 63 | 67.252 | 0.93678 | 855 | ||
| Synonymous | -0.0675 | 64 | 63.3 | 1.01 | 0.00000317 | 638 |
| Loss of Function | 2.18 | 4 | 12.2 | 0.328 | 6.14e-7 | 141 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle- stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol- calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling.;
Recessive Scores
- pRec
- 0.236
Intolerance Scores
- LoFtool
- 0.492
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 45.13
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.215
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |