P3H1

protein-coding

prolyl 3-hydroxylase 1, the group of Prolyl 3-hydroxylase family

Gene summary

This gene encodes an enzyme that is a member of the collagen prolyl hydroxylase family. These enzymes are localized to the endoplasmic reticulum and their activity is required for proper collagen synthesis and assembly. Mutations in this gene are associated with osteogenesis imperfecta type VIII. Three alternatively spliced transcript variants encoding different isoforms have been described. Other variants may exist, but their biological validity has not been determined. [provided by RefSeq, Aug 2011]

Previous symbols:

LEPRE1

MANE transcript

NM_022356.4

Inheritance

AR, AD

ClinVar variants

P:137U:298B:290

Top phenotype

Osteogenesis imperfecta, type VIII

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr1:42,746,335-42,767,084

External References & Databases

Ensembl (ENSG00000117385)

Transcript & Mutation Effects

hg38 • Region Span ~20.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

osteogenesis imperfecta type 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012581

Submitter: G2P

osteogenesis imperfecta type 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008147

Submitter: Orphanet

osteogenesis imperfecta type 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009804

Submitter: Orphanet

osteogenesis imperfecta type 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012581

Submitter: PanelApp Australia

osteogenesis imperfecta type 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012581

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Osteogenesis imperfecta, type VIIIAR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 17277775; 19088120; 22281939; 22608605; 23613367

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to P3H1 variants in ClinVar

10 Conditions Cataloged

Osteogenesis imperfecta type 8Total: 838

not providedTotal: 137

Inborn genetic diseasesTotal: 119

not specifiedTotal: 69

P3H1-related disorderTotal: 54

Osteogenesis Imperfecta, RecessiveTotal: 38

Osteogenesis imperfectaTotal: 33

P3H1-related disordersTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022356.4. 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			7 clinvar	270 clinvar	4 clinvar	281
missense		3 clinvar	286 clinvar	15 clinvar	1 clinvar	305
nonsense	26 clinvar	14 clinvar				40
start loss		2 clinvar				2
frameshift	39 clinvar	22 clinvar	1 clinvar			62
splice donor/acceptor (+/-2bp)	9 clinvar	22 clinvar	4 clinvar			35
Total	74	63	298	285	5	725

Highest pathogenic variant AF is 0.00012637589

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022356.4	RefSeq	NP_071751.3	15	MANE Select
ENST00000296388.10	Ensembl	ENSP00000296388.5	15	MANE Select
NM_001146289.2	RefSeq	NP_001139761.1	15	Standard
NM_001243246.2	RefSeq	NP_001230175.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Collagen biosynthesis and modifying enzymes
Collagen formation
Extracellular matrix organization

Biological Process

protein folding
negative regulation of cell population proliferation
positive regulation of neuron projection development
protein hydroxylation
peptidyl-proline hydroxylation

Molecular Function

molecular_function
iron ion binding
protein binding
collagen binding
procollagen-proline 3-dioxygenase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum lumen
membrane
protein-containing complex
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000236040
Coding exons: 14
Length: 20750
Individuals with no LoFs: 125619
Homozygous LoFs: 0
Heterozygous LoFs: 129
Defined: 125748
p: 0.000513

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.755	410	455	0.900	0.0000266	5179
Missense (PolyPhen)		120	131.27	0.91411		1487
Synonymous	0.527	181	190	0.951	0.0000116	1616
Loss of Function	0.481	32	35.1	0.912	0.00000190	400

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0034	0.0034	notable
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00033	0.00033	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00030	0.00030	rare
South Asian	0.00039	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Basement membrane-associated chondroitin sulfate proteoglycan (CSPG). Has prolyl 3-hydroxylase activity catalyzing the post-translational formation of 3-hydroxyproline in -Xaa-Pro- Gly- sequences in collagens, especially types IV and V. May be involved in the secretory pathway of cells. Has growth suppressive activity in fibroblasts. {ECO:0000269|PubMed:10951563}.;
Disease: DISEASE: Osteogenesis imperfecta 8 (OI8) [MIM:610915]: A form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI8 is characterized by disproportionate short stature, severe osteoporosis, shortening of the long bones, white sclerae, a round face and a short barrel- shaped chest. {ECO:0000269|PubMed:17277775, ECO:0000269|PubMed:19088120}. Note=The disease is caused by mutations affecting the gene represented in this entry. A splice site mutation leading to the absence of isoform 1 has been reported in 2 OI8 patients. Isoform 1 is the only form predicted to be located in the endoplasmic reticulum, which the appropriate location for the catalysis of collagen hydroxylation. These patients show indeed severely reduced COL1A1 hydroxylation (PubMed:19088120). {ECO:0000269|PubMed:19088120}.;

Recessive Scores

pRec: 0.128

Intolerance Scores

RVIS EVS: 0.36
RVIS percentile EVS: 74.68

Essentials

Essential (gene trap): N