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LHCGR

Chr 2ARAD

luteinizing hormone/choriogonadotropin receptor

Also known as: HHG, LCGR, LGR2, LH/CG-R, LH/CGR, LHR, LHRHR, LSH-R

NCBI Gene: 3973 UniProt: P22888

This receptor binds luteinizing hormone and choriogonadotropin, activating G protein-mediated adenylate cyclase signaling pathways. Mutations cause disorders of male secondary sexual development including precocious puberty, hypogonadotropic hypogonadism, Leydig cell hypoplasia with pseudohermaphroditism, and luteinizing hormone resistance in females. Inheritance can be either autosomal recessive or autosomal dominant depending on the specific phenotype.

Summary from RefSeq, OMIM, UniProt

Research Assistant →

Primary Disease Associations & Inheritance

Leydig cell adenoma, somatic, with precocious pubertyMIM #176410

Leydig cell hypoplasia with hypergonadotropic hypogonadismMIM #238320

Leydig cell hypoplasia with pseudohermaphroditismMIM #238320

Luteinizing hormone resistance, femaleMIM #238320

Precocious puberty, maleMIM #176410

UniProtFamilial male precocious puberty

Active trials

Pubs (1 yr)

108

P/LP submissions

46%

P/LP missense

0.89

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— LHCGR

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

68 unique Pathogenic / Likely Pathogenic· 149 VUS of 341 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — LHCGR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

ensembl: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.89LOEUF

pLI 0.000

Z-score 2.02

OE 0.58 (0.39–0.89)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

0.16Z-score

OE missense 0.98 (0.89–1.07)

350 obs / 358.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.58 (0.39–0.89)

0≤0.351.4

Missense OE0.98 (0.89–1.07)

0≤0.61.4

Synonymous OE1.00

0≤1.21.6

LoF obs/exp: 16 / 27.4Missense obs/exp: 350 / 358.7Syn Z: -0.04

0.78top 25%

GOF

0.77top 25%

LOF

0.2678th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction 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.

Literature Evidence

GOFWe showed that activating mutation of LHCGR likely plays important roles in the pathophysiology of PCOS involving abnormal reproductive physiology, whereas ALMS1 deficiency may promote anovulatory infertility via elevated androgens, suggesting that the disturbed LHCGR and ALMS1 cooperatively induce PMID:34147365

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.