GNRHR

Chr 4AR

gonadotropin releasing hormone receptor

Also known as: GNRHR1, GRHR, HH7, LHRHR, LRHR

NCBI Gene: 2798 ENSG00000109163 UniProt: P30968 OMIM: 138850

This gene encodes the gonadotropin-releasing hormone receptor, a G-protein coupled receptor that mediates GnRH signaling to stimulate release of luteinizing hormone and follicle-stimulating hormone from pituitary gonadotropes. Mutations cause autosomal recessive hypogonadotropic hypogonadism without anosmia, affecting reproductive hormone regulation and sexual development. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.75), and detailed clinical management guidance is available in GeneReviews.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.751 OMIM phenotype

Clinical Summary— GNRHR

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

44 unique Pathogenic / Likely Pathogenic· 122 VUS of 219 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GNRHR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.068

Z-score 2.18

OE 0.33 (0.16–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.30Z-score

OE missense 0.93 (0.82–1.07)

155 obs / 165.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.16–0.75)

0≤0.351.4

Missense OE?0.93 (0.82–1.07)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 4 / 12.2Missense obs/exp: 155 / 165.9Syn Z: -0.07

This gene — mechanism propensity

0.81top 10%

GOF

0.77top 25%

LOF

0.2092th %ile

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.

DNprediction above median

GOFprediction above median

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

219 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic26

VUS122

Likely Benign21

Benign22

Conflicting7

Pathogenic

Likely Pathogenic

122

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	12	0	0	18
Likely Pathogenic	8	18	0	0	26
VUS	0	57	62	3	122
Likely Benign	1	3	9	8	21
Benign	0	0	20	2	22
Conflicting	—				7
Total	15	90	91	13	216

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

17 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap GNRHR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →