GH1

protein-coding

growth hormone 1, the group of Growth hormone family

Gene summary

The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000515.5

Inheritance

AR, AD

ClinVar variants

P:22U:94B:43

Top phenotype

Isolated growth hormone deficiency, type IA; Isolated growth hormone deficiency, type 1B; Isolated growth hormone deficiency, type II; Kowarski syndrome

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr17:63,917,200-63,918,839

External References & Databases

Ensembl (ENSG00000259384)

Transcript & Mutation Effects

hg38 • Region Span ~1.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

isolated growth hormone deficiency type IASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009876

Submitter: PanelApp Australia

short stature due to growth hormone qualitative anomalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009879

Submitter: PanelApp Australia

isolated growth hormone deficiency type IISTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008250

Submitter: PanelApp Australia

isolated growth hormone deficiency type IISTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008250

Submitter: Labcorp Genetics (formerly Invitae)

isolated growth hormone deficiency type IISUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008250

Submitter: Orphanet

isolated growth hormone deficiency type IBSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013006

Submitter: Orphanet

isolated growth hormone deficiency type IASUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009876

Submitter: Orphanet

short stature due to growth hormone qualitative anomalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009879

Submitter: Orphanet

isolated growth hormone deficiency type IISTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008250

Submitter: Ambry Genetics

isolated growth hormone deficiency type IASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009876

Submitter: Labcorp Genetics (formerly Invitae)

isolated growth hormone deficiency type IADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009876

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Isolated growth hormone deficiency, type IA; Isolated growth hormone deficiency, type 1B; Isolated growth hormone deficiency, type II; Kowarski syndromeAD/AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Some individuals respond well to exogenous GH treatment, and benefits may be increased with early diagnosis and treatment

Refs: 7714096; 8530604; 9076339; 9024229; 9024235; 8552145; 9276733; 9435425; 10678654; 11443201; 12915652; 12655557; 15713716; 16060904; 15671105; 17785701; 18554279; 17925337; 20852587

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GH1 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 113

not specifiedTotal: 50

Decreased response to growth hormone stimulation testTotal: 38

Inborn genetic diseasesTotal: 35

Autosomal dominant isolated somatotropin deficiencyTotal: 26

Ateleiotic dwarfismTotal: 17

GH1-related disorderTotal: 12

Isolated growth hormone deficiency type IBTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000515.5. 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			6 clinvar	34 clinvar		40
missense	6 clinvar	6 clinvar	86 clinvar	9 clinvar		107
nonsense	1 clinvar					1
start loss						0
frameshift	2 clinvar		1 clinvar			3
splice donor/acceptor (+/-2bp)	5 clinvar	2 clinvar	1 clinvar			8
Total	14	8	94	43	0	159

Highest pathogenic variant AF is 0.0000065700433

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000515.5	RefSeq	NP_000506.2	5	MANE Select
ENST00000323322.10	Ensembl	ENSP00000312673.5	5	MANE Select
NM_022559.4	RefSeq	NP_072053.1	5	Standard
NM_022560.4	RefSeq	NP_072054.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gh1	Danio rerio	Structure: fat cell Quality: hypertrophic abnormal

Gene / Model

Organism

Observed Phenotype

gh1

Danio rerio

Structure: fat cell

Quality: hypertrophic

abnormal

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

positive regulation of receptor internalization
regulation of signaling receptor activity
positive regulation of activation of Janus kinase activity
positive regulation of glucose transmembrane transport
positive regulation of phosphatidylinositol 3-kinase signaling

Molecular Function

growth hormone receptor binding
prolactin receptor binding
hormone activity
protein binding
growth factor activity

Cellular Component

extracellular region
extracellular space
endosome lumen
collagen-containing extracellular matrix
growth hormone receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000323322
Coding exons: 5
Length: 1620
Individuals with no LoFs: 125735
Homozygous LoFs: 1
Heterozygous LoFs: 10
Defined: 125746
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.939	148	119	1.24	0.00000775	1411
Missense (PolyPhen)		32	33.366	0.95905		465
Synonymous	-2.80	81	54.7	1.48	0.00000386	429
Loss of Function	1.76	4	10.0	0.399	5.40e-7	107

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00020	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000026	0.000018	rare
South Asian	0.00013	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in growth control. Its major role in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-1. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.;
Disease: DISEASE: Growth hormone deficiency, isolated, 1A (IGHD1A) [MIM:262400]: An autosomal recessive, severe deficiency of growth hormone leading to dwarfism. Patients often develop antibodies to administered growth hormone. {ECO:0000269|PubMed:8364549}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Growth hormone deficiency, isolated, 1B (IGHD1B) [MIM:612781]: An autosomal recessive deficiency of growth hormone leading to short stature. Patients have low but detectable levels of growth hormone, significantly retarded bone age, and a positive response and immunologic tolerance to growth hormone therapy. {ECO:0000269|PubMed:12655557}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Kowarski syndrome (KWKS) [MIM:262650]: A syndrome clinically characterized by short stature associated with bioinactive growth hormone, normal or slightly increased growth hormone secretion, pathologically low insulin-like growth factor 1 levels, and normal catch-up growth on growth hormone replacement therapy. {ECO:0000269|PubMed:17519310, ECO:0000269|PubMed:8552145, ECO:0000269|PubMed:9276733}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Growth hormone deficiency, isolated, 2 (IGHD2) [MIM:173100]: An autosomal dominant deficiency of growth hormone leading to short stature. Clinical severity is variable. Patients have a positive response and immunologic tolerance to growth hormone therapy. {ECO:0000269|PubMed:11502836, ECO:0000269|PubMed:9152628}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.251

Intolerance Scores

LoFtool: 0.0442
RVIS EVS: 0.31
RVIS percentile EVS: 72.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.958

Gene Damage Prediction

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