GNRH1
Chr 8ARgonadotropin releasing hormone 1
Also known as: GNRH, GRH, LHRH, LNRH
This gene encodes gonadotropin-releasing hormone, which stimulates the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary gland. Mutations cause autosomal recessive hypogonadotropic hypogonadism with or without anosmia, affecting reproductive development and function. The gene shows relatively low constraint to loss-of-function variants (pLI 0.15).
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
143 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 2 | 0 | 77 | 0 | 79 |
Likely Pathogenic | 1 | 0 | 4 | 0 | 5 |
VUS | 0 | 11 | 18 | 1 | 30 |
Likely Benign | 0 | 0 | 8 | 2 | 10 |
Benign | 0 | 2 | 4 | 1 | 7 |
Conflicting | — | 6 | |||
| Total | 3 | 13 | 111 | 4 | 137 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
GNRH1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Neoadjuvant Degarelix With or Without Apalutamide (ARN-509) Followed by Radical Prostatectomy
ACTIVE NOT RECRUITINGHypofractionated, Dose Escalation Radiotherapy for High Risk Adenocarcinoma of the Prostate
ACTIVE NOT RECRUITINGElacestrant + Everolimus in Patients ER+/HER2-, ESR1mut, Advanced Breast Cancer Progressing to ET and CDK4/6i.
RECRUITINGNeoadjuvant Study Chemotherapy vs Letrozole + Abemaciclib in HR+/HER2- High/Intermediate Risk Breast Cancer Patients
ACTIVE NOT RECRUITINGSupraphysiologic Testosterone Priming Induces Darolutamide Extended Response
RECRUITINGExternal Resources
Links to major genomics databases and tools