GHRHR

protein-coding

growth hormone releasing hormone receptor, the group of Glucagon receptor family

Gene summary

This gene encodes a receptor for growth hormone-releasing hormone. Binding of this hormone to the receptor leads to synthesis and release of growth hormone. Mutations in this gene have been associated with isolated growth hormone deficiency (IGHD), also known as Dwarfism of Sindh, a disorder characterized by short stature. [provided by RefSeq, Jun 2010]

MANE transcript

NM_000823.4

Inheritance

ClinVar variants

P:43U:110B:91

Top phenotype

Isolated growth hormone deficiency, type IV

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr7:30,938,669-30,993,254

External References & Databases

Ensembl (ENSG00000106128)

Transcript & Mutation Effects

hg38 • Region Span ~54.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

isolated growth hormone deficiency, type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032567

Submitter: Labcorp Genetics (formerly Invitae)

isolated growth hormone deficiency, type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032567

Submitter: PanelApp Australia

isolated growth hormone deficiency type IBDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013006

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Isolated growth hormone deficiency, type IVAR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Combined treatment of GH and GNRHa can be effective in increasing final height, even in the case of advanced bone age and pubertal stage, though consideration related to cardiovascular-related treatment effects may be beneficial

Refs: 8528260; 11443201; 17925337; 19733620; 21274317; 21044116; 22423511; 21816782; 21292919; 22416078

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GHRHR variants in ClinVar

9 Conditions Cataloged

not providedTotal: 230

Inborn genetic diseasesTotal: 57

not specifiedTotal: 48

Isolated growth hormone deficiency type IBTotal: 38

Isolated growth hormone deficiency, type 4Total: 28

GHRHR-related disorderTotal: 14

Pituitary hormone deficiencyTotal: 3

Disorder of sexual differentiationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000823.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	5 clinvar	74 clinvar	2 clinvar	82
missense	4 clinvar	11 clinvar	101 clinvar	15 clinvar		131
nonsense	6 clinvar	2 clinvar				8
start loss			1 clinvar			1
frameshift	6 clinvar	4 clinvar	2 clinvar			12
splice donor/acceptor (+/-2bp)	6 clinvar	3 clinvar	1 clinvar			10
Total	22	21	110	89	2	244

Highest pathogenic variant AF is 0.0002051619

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000823.4	RefSeq	NP_000814.2	13	MANE Select
ENST00000326139.7	Ensembl	ENSP00000320180.2	13	MANE Select
ENST00000337750.9	Ensembl	ENSP00000338184.4	2	Standard
ENST00000396227.6	Ensembl	ENSP00000379529.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuroactive ligand-receptor interaction - Homo sapiens (human)
GPCRs, Other
GPCRs, Class B Secretin-like
Signaling by GPCR
Signal Transduction

Biological Process

cell surface receptor signaling pathway
G protein-coupled receptor signaling pathway
adenylate cyclase-activating G protein-coupled receptor signaling pathway
activation of adenylate cyclase activity
lactation

Molecular Function

G protein-coupled receptor activity
protein binding
G protein-coupled peptide receptor activity
growth hormone-releasing hormone receptor activity
peptide hormone binding

Cellular Component

nuclear inner membrane
nuclear outer membrane
cytoplasm
plasma membrane
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326139
Coding exons: 13
Length: 54586
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.497	262	240	1.09	0.0000148	2733
Missense (PolyPhen)		88	86.55	1.0168		1110
Synonymous	-1.77	121	98.7	1.23	0.00000643	845
Loss of Function	1.82	15	24.8	0.605	0.00000129	256

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for GRF, coupled to G proteins which activate adenylyl cyclase. Stimulates somatotroph cell growth, growth hormone gene transcription and growth hormone secretion.;

Recessive Scores

pRec: 0.223

Intolerance Scores

LoFtool: 0.824
RVIS EVS: -0.29
RVIS percentile EVS: 33.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.223

Gene Damage Prediction

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