GHR

protein-coding

growth hormone receptor, the group of Fibronectin type III domain containing

Gene summary

This gene encodes a member of the type I cytokine receptor family, which is a transmembrane receptor for growth hormone. Binding of growth hormone to the receptor leads to receptor dimerization and the activation of an intra- and intercellular signal transduction pathway leading to growth. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. In humans and rabbits, but not rodents, growth hormone binding protein (GHBP) is generated by proteolytic cleavage of the extracellular ligand-binding domain from the mature growth hormone receptor protein. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]

MANE transcript

NM_000163.5

Inheritance

AR, AD

ClinVar variants

P:65U:244B:172

Top phenotype

Growth hormone insensitivity syndrome (Laron syndrome)

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr5:42,423,439-42,721,878

External References & Databases

Ensembl (ENSG00000112964)

Transcript & Mutation Effects

hg38 • Region Span ~298.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Laron syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009877

Submitter: Orphanet

Laron syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009877

Submitter: G2P

short stature due to partial GHR deficiencySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0011420

Submitter: Orphanet

Laron syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009877

Submitter: Labcorp Genetics (formerly Invitae)

short stature due to partial GHR deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011420

Submitter: Labcorp Genetics (formerly Invitae)

short stature due to partial GHR deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011420

Submitter: PanelApp Australia

Laron syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009877

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Growth hormone insensitivity syndrome (Laron syndrome)AD/AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Medical treatment (eg, with recombinant human IGF1) can be beneficial

Refs: 5707789; 4470894; 1349669; 8488849; 7565946; 8784089; 9140387; 9024266; 9360502; 9851797; 11297575; 11468686; 12679461; 15001620; 17148568; 18404972; 18073295; 19789204; 20583548; 19812236; 20606392; 20962506; 21325617; 21396571; 21900382; 22117696; 22423513; 22587301; 23006617

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GHR variants in ClinVar

20 Conditions Cataloged

not providedTotal: 455

Laron-type isolated somatotropin defectTotal: 87

Inborn genetic diseasesTotal: 71

not specifiedTotal: 61

Short stature due to partial GHR deficiencyTotal: 32

GHR-related disorderTotal: 22

Hypercholesterolemia, familial, 1Total: 16

Growth hormone insensitivity syndromeTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000163.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	2 clinvar	1 clinvar	6 clinvar	145 clinvar		154
missense	8 clinvar	10 clinvar	227 clinvar	24 clinvar	3 clinvar	272
nonsense	14 clinvar	2 clinvar	1 clinvar			17
start loss	2 clinvar					2
frameshift	11 clinvar	4 clinvar	8 clinvar			23
splice donor/acceptor (+/-2bp)	8 clinvar	3 clinvar	2 clinvar			13
Total	45	20	244	169	3	481

Highest pathogenic variant AF is 0.00005882852

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000163.5	RefSeq	NP_000154.1	9	MANE Select
ENST00000230882.9	Ensembl	ENSP00000230882.4	9	MANE Select
NM_001242399.2	RefSeq	NP_001229328.1	10	Standard
NM_001242400.2	RefSeq	NP_001229329.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Jak-STAT signaling pathway - Homo sapiens (human)
Neuroactive ligand-receptor interaction - Homo sapiens (human)
Cytokine-cytokine receptor interaction - Homo sapiens (human)
JAK-STAT-Core

Biological Process

activation of MAPK activity
endocytosis
JAK-STAT cascade
cytokine-mediated signaling pathway
taurine metabolic process

Molecular Function

cytokine receptor activity
growth hormone receptor activity
protein binding
peptide hormone binding
growth factor binding

Cellular Component

extracellular region
extracellular space
cytosol
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000230882
Coding exons: 9
Length: 298101
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 40
Defined: 125748
p: 0.000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.361	346	328	1.06	0.0000158	4222
Missense (PolyPhen)		137	142.31	0.96269		1889
Synonymous	-0.305	125	121	1.04	0.00000618	1199
Loss of Function	2.97	12	29.4	0.408	0.00000145	360

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity). {ECO:0000250}.; FUNCTION: Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.;
Disease: DISEASE: Laron syndrome (LARS) [MIM:262500]: A severe form of growth hormone insensitivity characterized by growth impairment, short stature, dysfunctional growth hormone receptor, and failure to generate insulin-like growth factor I in response to growth hormone. {ECO:0000269|PubMed:10870033, ECO:0000269|PubMed:14678285, ECO:0000269|PubMed:2779634, ECO:0000269|PubMed:8137822, ECO:0000269|PubMed:8450064, ECO:0000269|PubMed:8504296, ECO:0000269|PubMed:9024232, ECO:0000269|PubMed:9661642, ECO:0000269|PubMed:9851797}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Growth hormone insensitivity, partial (GHIP) [MIM:604271]: A disease characterized by partial resistance to growth hormone resulting in short stature. Short stature is defined by a standing height more than 2 standard deviations below the mean (or below the 2.5 percentile) for sex and chronological age, compared with a well-nourished, healthy, genetically relevant population. {ECO:0000269|PubMed:7565946}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.528

Intolerance Scores

LoFtool: 0.210
RVIS EVS: 0.76
RVIS percentile EVS: 86.8

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.579

Gene Damage Prediction

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