GNRH1

gonadotropin releasing hormone 1, the group of Neuropeptides

Basic information

Region (hg38): 8:25419257-25424654

Previous symbols: [ "GRH", "GNRH", "LHRH" ]

Links

ENSG00000147437 ∙ NCBI:2796 ∙ OMIM:152760 ∙ HGNC:4419 ∙ Uniprot:P01148 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypogonadotropic hypogonadism (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 12 with or without anosmia (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 12 with or without anosmia	AR/Digenic	Endocrine	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	Endocrine; Genitourinary; Neurologic	19535795; 19567835; 20301509; 20389089; 20887715; 21722705
Digenic inheritance (with NR0B1) has been reported;

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GNRH1 gene.

• not provided (19 variants)
• Hypogonadotropic hypogonadism 12 with or without anosmia (15 variants)
• Isolated GnRH Deficiency (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GNRH1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	1	1	3
missense	2		4		2	8
nonsense						0
start loss						0
frameshift	1					1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding			10	6	2	18
Total	3	0	15	7	5

Highest pathogenic variant AF is 0.0000197

Variants in GNRH1

This is a list of pathogenic ClinVar variants found in the GNRH1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
8-25419428-C-A			Conflicting classifications of pathogenicity (Dec 28, 2023)
8-25419460-C-G			Benign (Nov 27, 2023)
8-25419472-A-G		Hypogonadotropic hypogonadism 12 with or without anosmia	Uncertain significance (Jan 13, 2018)
8-25419625-G-GT			Likely benign (Aug 10, 2019)
8-25421565-T-G		Hypogonadotropic hypogonadism 12 with or without anosmia	Conflicting classifications of pathogenicity (Oct 28, 2023)
8-25421600-A-T		Hypogonadotropic hypogonadism 12 with or without anosmia	Uncertain significance (Jan 13, 2018)
8-25421616-G-A			Uncertain significance (Aug 30, 2022)
8-25421627-G-A		Hypogonadotropic hypogonadism 12 with or without anosmia	Benign (Dec 22, 2023)
8-25421632-G-A			Uncertain significance (Sep 22, 2021)
8-25421633-T-C		Hypogonadotropic hypogonadism 12 with or without anosmia	Conflicting classifications of pathogenicity (Apr 04, 2018)
8-25421667-A-C		Amenorrhea	Uncertain significance (Mar 08, 2021)
8-25422909-T-C			Likely benign (Aug 14, 2018)
8-25422988-T-C			Likely benign (Apr 06, 2020)
8-25423105-T-C			Benign (Nov 05, 2018)
8-25423150-A-C			Benign (Jun 26, 2018)
8-25423190-C-G		Hypogonadotropic hypogonadism 12 with or without anosmia	Conflicting classifications of pathogenicity (Jan 18, 2024)
8-25423239-C-T		Hypogonadotropic hypogonadism 12 with or without anosmia	Pathogenic/Likely pathogenic (Mar 29, 2024)
8-25423240-G-A			Pathogenic (May 20, 2023)
8-25423243-GT-G			Uncertain significance (Jul 14, 2009)
8-25423245-C-T			Uncertain significance (Nov 07, 2022)
8-25423258-G-C			Uncertain significance (Dec 07, 2022)
8-25423268-G-A			Likely benign (Feb 24, 2022)
8-25423270-A-AG			Pathogenic (Dec 15, 2022)
8-25423279-C-T			Uncertain significance (Jan 14, 2024)
8-25423284-C-G		Hypogonadotropic hypogonadism 12 with or without anosmia	Benign (Jan 29, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GNRH1	protein_coding	protein_coding	ENST00000276414	3	5395

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.151	0.784	124754	0	5	124759	0.0000200

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.164	49	52.3	0.936	0.00000320	582
Missense in Polyphen		11	12.39	0.88784		150
Synonymous	0.0472	18	18.3	0.986	9.53e-7	181
Loss of Function	1.51	2	5.97	0.335	3.42e-7	55

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000444	0.0000441
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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}.
• Pathway: GnRH signaling pathway - Homo sapiens (human);Hormonal control of Pubertal Growth Spurt;Signaling by GPCR;Signal Transduction;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Hormone ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;GPCR signaling-G alpha i;G alpha (q) signalling events;GPCR downstream signalling;Nongenotropic Androgen signaling (Consensus)

Recessive Scores

• pRec: 0.642

Intolerance Scores

• loftool: 0.618
• rvis_EVS: 0.68
• rvis_percentile_EVS: 84.81

Haploinsufficiency Scores

• pHI: 0.0309
• hipred: N
• hipred_score: 0.171

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.673

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gnrh1
• Phenotype: homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); renal/urinary system phenotype; immune system phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); neoplasm; hematopoietic system phenotype; reproductive system phenotype; normal phenotype; liver/biliary system phenotype

Gene ontology

• Biological process: reproduction;signal transduction;G protein-coupled receptor signaling pathway;cell-cell signaling;multicellular organism development;female pregnancy;aging;negative regulation of cell population proliferation;regulation of gene expression;regulation of signaling receptor activity;male sex determination;response to corticosteroid;response to lipopolysaccharide;negative regulation of immature T cell proliferation;response to testosterone;response to prostaglandin E;response to potassium ion;negative regulation of apoptotic process;estrous cycle;response to ethanol;response to prolactin;regulation of ovarian follicle development;negative regulation of neuron migration
• Cellular component: extracellular region;extracellular space;mitochondrion;Golgi-associated vesicle;dendrite;perikaryon;axon terminus;cytoplasmic side of rough endoplasmic reticulum membrane;neurosecretory vesicle
• Molecular function: hormone activity;gonadotropin hormone-releasing hormone activity;gonadotropin-releasing hormone receptor binding