LHCGR

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

Basic information

Region (hg38): 2:48686773-48755730

Previous symbols: [ "HHG" ]

Links

ENSG00000138039 ∙ NCBI:3973 ∙ OMIM:152790 ∙ HGNC:6585 ∙ Uniprot:P22888 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial male-limited precocious puberty (Supportive), mode of inheritance: AD
• Leydig cell hypoplasia, type 1 (Strong), mode of inheritance: AR
• familial male-limited precocious puberty (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Leydig cell hypoplasia type I; Leydig cell hypoplasia type II; Luteinizing hormone resistance, female; Precocious puberty, male	AR	Endocrine; Genitourinary; Oncologic	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	Endocrine; Genitourinary; Oncologic	184390; 6792847; 3557461; 3812586; 2492636; 7692306; 7719343; 7581384; 8559204; 8923827; 9703386; 9817592; 10580072; 10714363; 10704433; 11391350; 11857565; 19129711; 21060208; 21683950; 21720050; 22369774; 22931948
Both germline and somatic variants have been described

ClinVar

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

• not provided (121 variants)
• Leydig cell agenesis (73 variants)
• Gonadotropin-independent familial sexual precocity (69 variants)
• Hypergonadotropic hypogonadism (33 variants)
• Inborn genetic diseases (14 variants)
• not specified (13 variants)
• LHCGR-related condition (3 variants)
• Leydig cell agenesis;Gonadotropin-independent familial sexual precocity (2 variants)
• Gonadotropin-independent familial sexual precocity;Leydig cell agenesis (2 variants)
• Luteinizing hormone resistance, female (1 variants)
• Precocious puberty in males (1 variants)
• See cases (1 variants)
• Leydig hypoplasia, type I (1 variants)
• 46,XY sex reversal 11 (1 variants)
• Luteinizing hormone/choriogonadotropin receptor, lq variant (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LHCGR 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			4	9	4	17
missense	7	6	38	6	2	59
nonsense	4	3				7
start loss						0
frameshift	1					1
inframe indel			3		1	4
splice donor/acceptor (+/-2bp)	1	2				3
splice region				2	1	3
non coding			15	16	34	65
Total	13	11	60	31	41

Highest pathogenic variant AF is 0.0000592

Variants in LHCGR

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

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

Position	Type	Phenotype	Significance	ClinVar
2-48686803-C-A		Gonadotropin-independent familial sexual precocity • Leydig cell agenesis	Uncertain significance (Jan 13, 2018)
2-48686892-T-C		Gonadotropin-independent familial sexual precocity • Leydig cell agenesis	Uncertain significance (Jan 13, 2018)
2-48686950-G-T		Gonadotropin-independent familial sexual precocity • Leydig cell agenesis	Uncertain significance (Jan 13, 2018)
2-48686973-A-G		Leydig cell agenesis • Gonadotropin-independent familial sexual precocity • Hypergonadotropic hypogonadism	Uncertain significance (Jan 12, 2018)
2-48686987-T-C		Gonadotropin-independent familial sexual precocity • Leydig cell agenesis	Uncertain significance (Jan 12, 2018)
2-48687120-A-T		Gonadotropin-independent familial sexual precocity • Hypergonadotropic hypogonadism • Leydig cell agenesis	Conflicting classifications of pathogenicity (Jan 12, 2018)
2-48687144-T-A		Leydig cell agenesis • Gonadotropin-independent familial sexual precocity	Uncertain significance (Jan 13, 2018)
2-48687162-C-T		Leydig cell agenesis • Gonadotropin-independent familial sexual precocity • Hypergonadotropic hypogonadism	Benign/Likely benign (Jan 13, 2018)
2-48687169-A-G		Hypergonadotropic hypogonadism • Leydig cell agenesis • Gonadotropin-independent familial sexual precocity	Benign (May 13, 2021)
2-48687185-G-A		Gonadotropin-independent familial sexual precocity • Leydig cell agenesis	Conflicting classifications of pathogenicity (Jan 12, 2018)
2-48687254-G-A		Leydig cell agenesis • Gonadotropin-independent familial sexual precocity	Uncertain significance (Jan 12, 2018)
2-48687283-A-G		Leydig cell agenesis • Gonadotropin-independent familial sexual precocity	Uncertain significance (Jan 12, 2018)
2-48687314-G-T		Gonadotropin-independent familial sexual precocity • Leydig cell agenesis • Hypergonadotropic hypogonadism	Uncertain significance (Jan 12, 2018)
2-48687337-C-T		Gonadotropin-independent familial sexual precocity • Leydig cell agenesis • Hypergonadotropic hypogonadism	Benign (May 13, 2021)
2-48687397-A-T		Leydig cell agenesis • Hypergonadotropic hypogonadism • Gonadotropin-independent familial sexual precocity	Uncertain significance (Jan 13, 2018)
2-48687415-GT-G		Gonadotropin-independent familial sexual precocity • Leydig cell agenesis • Hypergonadotropic hypogonadism	Likely benign (Jun 14, 2016)
2-48687424-A-G		Gonadotropin-independent familial sexual precocity • Hypergonadotropic hypogonadism • Leydig cell agenesis	Uncertain significance (Jan 13, 2018)
2-48687476-C-G		Leydig cell agenesis • Hypergonadotropic hypogonadism • Gonadotropin-independent familial sexual precocity	Benign (Jun 26, 2018)
2-48687505-A-G		Leydig cell agenesis • Gonadotropin-independent familial sexual precocity	Uncertain significance (Jan 12, 2018)
2-48687515-A-G		Leydig cell agenesis • Gonadotropin-independent familial sexual precocity	Uncertain significance (Jan 12, 2018)
2-48687549-A-G		Gonadotropin-independent familial sexual precocity • Hypergonadotropic hypogonadism • Leydig cell agenesis	Benign (Aug 12, 2018)
2-48687566-G-A		Leydig cell agenesis • Hypergonadotropic hypogonadism • Gonadotropin-independent familial sexual precocity	Benign/Likely benign (Nov 08, 2018)
2-48687643-A-AT			Likely benign (Oct 18, 2020)
2-48687675-A-C		Gonadotropin-independent familial sexual precocity • Leydig cell agenesis	Benign/Likely benign (Jan 12, 2018)
2-48687690-G-A		Hypergonadotropic hypogonadism • Gonadotropin-independent familial sexual precocity • Leydig cell agenesis	Conflicting classifications of pathogenicity (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LHCGR	protein_coding	protein_coding	ENST00000294954	11	123453

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.30e-8	0.962	125691	0	57	125748	0.000227

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.163	350	359	0.976	0.0000182	4543
Missense in Polyphen		110	120.06	0.91621		1604
Synonymous	-0.0419	141	140	1.00	0.00000726	1398
Loss of Function	2.02	16	27.4	0.584	0.00000142	353

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000358	0.000358
Ashkenazi Jewish	0.000397	0.000397
East Asian	0.00	0.00
Finnish	0.000185	0.000185
European (Non-Finnish)	0.000291	0.000290
Middle Eastern	0.00	0.00
South Asian	0.000131	0.000131
Other	0.000490	0.000489

dbNSFP

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.
• Pathway: 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;Peptide GPCRs;Ovarian Infertility Genes;GPCRs, Class A Rhodopsin-like;Signaling by GPCR;Signal Transduction;G alpha (s) signalling events;Hormone ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;GPCR downstream signalling;Arf6 signaling events (Consensus)

Recessive Scores

• pRec: 0.426

Intolerance Scores

• loftool: 0.283
• rvis_EVS: 0.36
• rvis_percentile_EVS: 74.63

Haploinsufficiency Scores

• pHI: 0.130
• hipred: N
• hipred_score: 0.410
• ghis: 0.441

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.668

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Lhcgr
• 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); limbs/digits/tail phenotype; digestive/alimentary phenotype; renal/urinary system phenotype; skeleton phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; normal phenotype; reproductive system phenotype; growth/size/body region phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; cellular phenotype; homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: lhcgr
• Affected structure: postovulatory follicle
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• 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;male gonad development;hormone-mediated signaling pathway;ovulation cycle process;male genitalia development;positive regulation of inositol trisphosphate biosynthetic process;luteinizing hormone signaling pathway;positive regulation of adenylate cyclase activity;cognition;cellular response to gonadotropin stimulus;cellular response to luteinizing hormone stimulus
• Cellular component: endosome;plasma membrane;integral component of plasma membrane
• Molecular function: luteinizing hormone receptor activity;G protein-coupled peptide receptor activity;choriogonadotropin hormone receptor activity;choriogonadotropin hormone binding