GeneBe

LHCGR

protein-coding

luteinizing hormone/choriogonadotropin receptor, the group of Glycoprotein hormone receptors

Gene summary

This gene encodes the receptor for both luteinizing hormone and choriogonadotropin. This receptor belongs to the G-protein coupled receptor 1 family, and its activity is mediated by G proteins which activate adenylate cyclase. Mutations in this gene result in disorders of male secondary sexual character development, including familial male precocious puberty, also known as testotoxicosis, hypogonadotropic hypogonadism, Leydig cell adenoma with precocious puberty, and male pseudohermaphtoditism with Leydig cell hypoplasia. [provided by RefSeq, Jul 2008]

Previous symbols:
  • HHG

MANE transcript

NM_000233.4

Inheritance

AD, AR

ClinVar variants

P:59U:121B:45

Top phenotype

Leydig cell hypoplasia type I; Leydig cell hypoplasia type II; Luteinizing hormone resistance, female; Precocious puberty, male

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr2:48,686,774-48,755,730

External References & Databases

Ensembl (ENSG00000138039)NCBI Gene (3973)OMIM (152790)HGNC:6585GenCCUniProt (P22888)AlphaFoldClinVar (LHCGR)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~69.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial male-limited precocious pubertySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008303

Submitter: Orphanet

familial male-limited precocious pubertySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008303

Submitter: Labcorp Genetics (formerly Invitae)

Leydig cell hypoplasia, type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009384

Submitter: Labcorp Genetics (formerly Invitae)

Leydig cell hypoplasia, type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009384

Submitter: PanelApp Australia

familial male-limited precocious pubertySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008303

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Leydig cell hypoplasia type I; Leydig cell hypoplasia type II; Luteinizing hormone resistance, female; Precocious puberty, maleAR

Manifestation: Endocrine; Genitourinary; Oncologic

Intervention: Endocrine; Genitourinary; Oncologic

Rationale: In mild forms of LCH, the disorder may not be clinically recognized early, and exogenous testosterone can result in normal virilization; In Precocious puberty, male, medical therapy (eg, with combined spironolactone and testolactone) has been reported as beneficial; Surveillance for related neoplasms (eg, testicular neoplasms) may allow prompt diagnosis and treatment

Comments: Both germline and somatic variants have been described

Refs: 184390; 6792847; 3557461; 3812586; 2492636; 7692306; 7719343; 7581384; 8559204; 8923827; 9703386; 9817592; 10580072; 10714363; 10704433; 11391350; 11857565; 19129711; 21060208; 21683950; 21720050; 22369774; 22931948Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LHCGR variants in ClinVar

15 Conditions Cataloged
not providedTotal: 143
Inborn genetic diseasesTotal: 72
Leydig cell agenesisTotal: 65
Gonadotropin-independent familial sexual precocityTotal: 54
LHCGR-related disorderTotal: 25
not specifiedTotal: 18
Luteinizing hormone resistance, femaleTotal: 4
Leydig cell hypoplasia, type IITotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000233.4. 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
3
clinvar
27
clinvar
2
clinvar
 32
missense
18
clinvar
16
clinvar
118
clinvar
16
clinvar
 168
nonsense
5
clinvar
5
clinvar
 10
start loss
0
frameshift
1
clinvar
6
clinvar
 7
splice donor/acceptor (+/-2bp)
4
clinvar
4
clinvar
 8
Total2831121432225

Highest pathogenic variant AF is 0.000093213326

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000233.4RefSeqNP_000224.211MANE Select
ENST00000294954.12EnsemblENSP00000294954.611MANE Select
ENST00000401907.5EnsemblENSP00000385406.111Standard
ENST00000401907.6EnsemblENSP00000385406.111Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
lhcgrDanio rerio

Structure: postovulatory follicle

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Calcium signaling pathway - Homo sapiens (human)
  • Prolactin signaling pathway - Homo sapiens (human)
  • Neuroactive ligand-receptor interaction - Homo sapiens (human)
  • Ovarian steroidogenesis - Homo sapiens (human)
  • Intracellular Signalling Through LHCGR Receptor and Luteinizing Hormone/Choriogonadotropin

Biological Process

  • G protein-coupled receptor signaling pathway
  • G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
  • adenylate cyclase-activating G protein-coupled receptor signaling pathway
  • activation of adenylate cyclase activity
  • phospholipase C-activating G protein-coupled receptor signaling pathway

Molecular Function

  • luteinizing hormone receptor activity
  • G protein-coupled peptide receptor activity
  • choriogonadotropin hormone receptor activity
  • choriogonadotropin hormone binding

Cellular Component

  • endosome
  • plasma membrane
  • integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000294954
Coding exons
11
Length
123453
Individuals with no LoFs
125691
Homozygous LoFs
0
Heterozygous LoFs
57
Defined
125748
p
0.000227
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1633503590.9760.00001824543
Missense (PolyPhen)110120.060.916211604
Synonymous-0.04191411401.000.000007261398
Loss of Function2.021627.40.5840.00000142353

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish0.000400.00040rare
East Asian00.0absent
Finnish0.000180.00018rare
European (Non-Finnish)0.000290.00029rare
South Asian0.000130.00013rare
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Receptor for lutropin-choriogonadotropic hormone (PubMed:11847099). The activity of this receptor is mediated by G proteins which activate adenylate cyclase (PubMed:11847099). {ECO:0000269|PubMed:11847099}.;
Disease
DISEASE: Familial male precocious puberty (FMPP) [MIM:176410]: In FMPP the receptor is constitutively activated. {ECO:0000269|PubMed:11134146, ECO:0000269|PubMed:11391350, ECO:0000269|PubMed:7629248, ECO:0000269|PubMed:7692306, ECO:0000269|PubMed:7714085, ECO:0000269|PubMed:7757065, ECO:0000269|PubMed:8281137, ECO:0000269|PubMed:8829636, ECO:0000269|PubMed:8929952, ECO:0000269|PubMed:9467560, ECO:0000269|PubMed:9661624}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Luteinizing hormone resistance (LHR) [MIM:238320]: An autosomal recessive disorder characterized by unresponsiveness to luteinizing hormone, defective sexual development in males, and defective follicular development and ovulation, amenorrhea and infertility in females. Two forms of the disorder have been defined in males. Type 1 is a severe form characterized by complete 46,XY male pseudohermaphroditism, low testosterone and high luteinizing hormone levels, total lack of responsiveness to luteinizing and chorionic gonadotropin hormones, lack of breast development, and absent development of secondary male sex characteristics. Type 2, a milder form, displays a broader range of phenotypic expression ranging from micropenis to severe hypospadias. {ECO:0000269|PubMed:12050206, ECO:0000269|PubMed:15372531, ECO:0000269|PubMed:15472221, ECO:0000269|PubMed:19551906, ECO:0000269|PubMed:7719343, ECO:0000269|PubMed:8559204, ECO:0000269|PubMed:9215288, ECO:0000269|PubMed:9514160, ECO:0000269|PubMed:9626144, ECO:0000269|PubMed:9626653}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.426

Intolerance Scores

LoFtool
0.283
RVIS EVS
0.36
RVIS percentile EVS
74.63

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.668

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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