GeneBe

PLOD3

protein-coding

procollagen-lysine,2-oxoglutarate 5-dioxygenase 3, the group of Procollagen-lysine,2-oxoglutarate 5-dioxygenase family

Gene summary

The protein encoded by this gene is a membrane-bound homodimeric enzyme that is localized to the cisternae of the rough endoplasmic reticulum. The enzyme (cofactors iron and ascorbate) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. The resultant hydroxylysyl groups are attachment sites for carbohydrates in collagen and thus are critical for the stability of intermolecular crosslinks. Some patients with Ehlers-Danlos syndrome type VIB have deficiencies in lysyl hydroxylase activity. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001084.5

Inheritance

AR

ClinVar variants

P:38U:271B:239

Top phenotype

Bone fragility with contractures, arterial rupture, and deafness (BCARD syndrome)

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr7:101,205,977-101,218,420

External References & Databases

Ensembl (ENSG00000106397)NCBI Gene (8985)OMIM (603066)HGNC:9083GenCCUniProt (O60568)AlphaFoldClinVar (PLOD3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~12.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

bone fragility with contractures, arterial rupture, and deafnessSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012892

Submitter: PanelApp Australia

bone fragility with contractures, arterial rupture, and deafnessMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012892

Submitter: Ambry Genetics

bone fragility with contractures, arterial rupture, and deafnessSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012892

Submitter: Labcorp Genetics (formerly Invitae)

bone fragility with contractures, arterial rupture, and deafnessLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012892

Submitter: G2P

Clinical Genomic Database (CGD)

Bone fragility with contractures, arterial rupture, and deafness (BCARD syndrome)AR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Musculoskeletal; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: The condition may be clinically recognizable in most individuals, but recognition may allow surveillance for and prompt treatment of vascular anomalies; Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 18834968Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLOD3 variants in ClinVar

8 Conditions Cataloged
not providedTotal: 651
Inborn genetic diseasesTotal: 130
PLOD3-related disorderTotal: 45
not specifiedTotal: 39
Bone fragility with contractures, arterial rupture, and deafnessTotal: 32
Hemorrhage, intracerebral, susceptibility toTotal: 3
Congenital portosystemic shuntTotal: 2
Neurodevelopmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001084.5. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
185
clinvar
10
clinvar
 198
missense
2
clinvar
261
clinvar
41
clinvar
3
clinvar
 307
nonsense
6
clinvar
2
clinvar
1
clinvar
 9
start loss
0
frameshift
13
clinvar
1
clinvar
3
clinvar
 17
splice donor/acceptor (+/-2bp)
1
clinvar
13
clinvar
3
clinvar
 17
Total201827122613548

Highest pathogenic variant AF is 0.000041727948

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001084.5RefSeqNP_001075.119MANE Select
ENST00000223127.8EnsemblENSP00000223127.319MANE Select
ENST00000414785.5EnsemblENSP00000407551.14Standard
ENST00000421736.1EnsemblENSP00000407908.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
plod3Danio rerio

Structure: CaP motoneuron

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysine degradation - Homo sapiens (human)
  • Other types of O-glycan biosynthesis - Homo sapiens (human)
  • Collagen biosynthesis and modifying enzymes
  • Collagen formation
  • Extracellular matrix organization

Biological Process

  • in utero embryonic development
  • endothelial cell morphogenesis
  • protein O-linked glycosylation
  • protein localization
  • peptidyl-lysine hydroxylation

Molecular Function

  • iron ion binding
  • protein binding
  • procollagen-lysine 5-dioxygenase activity
  • L-ascorbic acid binding
  • procollagen glucosyltransferase activity

Cellular Component

  • extracellular space
  • endoplasmic reticulum
  • endoplasmic reticulum lumen
  • endoplasmic reticulum membrane
  • rough endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000223127
Coding exons
19
Length
12444
Individuals with no LoFs
125667
Homozygous LoFs
0
Heterozygous LoFs
81
Defined
125748
p
0.000322
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.1584544640.9790.00003244743
Missense (PolyPhen)92106.170.866571077
Synonymous-0.3232021961.030.00001441476
Loss of Function2.542745.40.5940.00000249459

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000440.00043rare
Latino/Admixed American0.000530.00052rare
Ashkenazi Jewish00.0absent
East Asian0.000440.00044rare
Finnish0.000190.00018rare
European (Non-Finnish)0.000300.00030rare
South Asian0.000230.00023rare
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens. These hydroxylysines serve as sites of attachment for carbohydrate units and are essential for the stability of the intermolecular collagen cross-links. {ECO:0000250|UniProtKB:P24802}.;
Disease
DISEASE: Lysyl hydroxylase 3 deficiency (LH3 deficiency) [MIM:612394]: Connective tissue disorder. The syndrome is characterized by congenital malformations severely affecting many tissues and organs and revealing features of several collagen disorders, most of them involving COL2A1 (type II collagen). The findings suggest that the failure of lysyl hydroxylation and hydroxylysyl carbohydrate addition, which affects many collagens, is the molecular basis of this syndrome. {ECO:0000269|PubMed:18834968}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.342

Intolerance Scores

LoFtool
0.242
RVIS EVS
-1.12
RVIS percentile EVS
6.58

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.652

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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