GeneBe

GNRH1

protein-coding

gonadotropin releasing hormone 1, the group of Neuropeptides

Gene summary

This gene encodes a preproprotein that is proteolytically processed to generate a peptide that is a member of the gonadotropin-releasing hormone (GnRH) family of peptides. Alternative splicing results in multiple transcript variants, at least one of which is secreted and then cleaved to generate gonadoliberin-1 and GnRH-associated peptide 1. Gonadoliberin-1 stimulates the release of luteinizing and follicle stimulating hormones, which are important for reproduction. Mutations in this gene are associated with hypogonadotropic hypogonadism. [provided by RefSeq, Nov 2015]

Previous symbols:
  • GRH
  • GNRH
  • LHRH

MANE transcript

NM_001083111.2

Inheritance

AR, AD, Digenic

ClinVar variants

P:6U:13B:7

Top phenotype

Hypogonadotropic hypogonadism 12 with or without anosmia

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr8:25,419,258-25,424,654

External References & Databases

Ensembl (ENSG00000147437)NCBI Gene (2796)OMIM (152760)HGNC:4419GenCCUniProt (P01148)AlphaFoldClinVar (GNRH1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypogonadotropic hypogonadism 12 with or without anosmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013914

Submitter: Ambry Genetics

hypogonadotropic hypogonadismLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018555

Submitter: Ambry Genetics

hypogonadotropic hypogonadism 12 with or without anosmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013914

Submitter: PanelApp Australia

hypogonadotropic hypogonadismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018555

Submitter: Orphanet

hypogonadotropic hypogonadism 12 with or without anosmiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013914

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 12 with or without anosmiaAR/Digenic

Manifestation: Endocrine; Genitourinary; Neurologic

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 NR0B1) has been reported;

Refs: 19535795; 19567835; 20301509; 20389089; 20887715; 21722705Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNRH1 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 24
Hypogonadotropic hypogonadism 12 with or without anosmiaTotal: 16
not specifiedTotal: 5
Hypogonadotropic hypogonadismTotal: 2
AmenorrheaTotal: 1
GNRH1-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001083111.2. 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
3
clinvar
1
clinvar
 6
missense
2
clinvar
10
clinvar
2
clinvar
1
clinvar
 15
nonsense
1
clinvar
 1
start loss
0
frameshift
2
clinvar
2
clinvar
 4
splice donor/acceptor (+/-2bp)
0
Total24135226

Highest pathogenic variant AF is 0.000021917207

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001083111.2RefSeqNP_001076580.13MANE Select
ENST00000421054.7EnsemblENSP00000391280.23MANE Select
NM_000825.3RefSeqNP_000816.43Standard
ENST00000276414.4EnsemblENSP00000276414.43Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • GnRH signaling pathway - Homo sapiens (human)
  • Hormonal control of Pubertal Growth Spurt
  • Signaling by GPCR
  • Signal Transduction
  • GPCR signaling-G alpha q

Biological Process

  • reproduction
  • signal transduction
  • G protein-coupled receptor signaling pathway
  • cell-cell signaling
  • multicellular organism development

Molecular Function

  • hormone activity
  • gonadotropin hormone-releasing hormone activity
  • gonadotropin-releasing hormone receptor binding

Cellular Component

  • extracellular region
  • extracellular space
  • mitochondrion
  • Golgi-associated vesicle
  • dendrite

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000276414
Coding exons
3
Length
5395
Individuals with no LoFs
124754
Homozygous LoFs
0
Heterozygous LoFs
5
Defined
124759
p
0.0000200
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1644952.30.9360.00000320582
Missense (PolyPhen)1112.390.88784150
Synonymous0.04721818.30.9869.53e-7181
Loss of Function1.5125.970.3353.42e-755

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000440.000044rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.;
Disease
DISEASE: Hypogonadotropic hypogonadism 12 with or without anosmia (HH12) [MIM:614841]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:19535795, ECO:0000269|PubMed:23643382}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in GNRH1 as well as in other HH- associated genes including PROKR2 and FGFR1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.;

Recessive Scores

pRec
0.642

Intolerance Scores

LoFtool
0.618
RVIS EVS
0.68
RVIS percentile EVS
84.81

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.673

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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