PLOD2

protein-coding

procollagen-lysine,2-oxoglutarate 5-dioxygenase 2, 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. Mutations in the coding region of this gene are associated with Bruck syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MANE transcript

NM_182943.3

Inheritance

ClinVar variants

P:44U:207B:84

Top phenotype

Bruck syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr3:146,035,139-146,163,725

External References & Databases

Ensembl (ENSG00000152952)

Transcript & Mutation Effects

hg38 • Region Span ~128.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bruck syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012217

Submitter: G2P

Bruck syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012217

Submitter: PanelApp Australia

Bruck syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017195

Submitter: Orphanet

Bruck syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012217

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Bruck syndrome 2AR

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: 12881513; 15523624; 22689593

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLOD2 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 342

Inborn genetic diseasesTotal: 89

Bruck syndrome 2Total: 66

not specifiedTotal: 52

PLOD2-related disorderTotal: 22

Osteogenesis imperfectaTotal: 21

Short femurTotal: 2

CamptodactylyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182943.3. 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	68 clinvar		75
missense	3 clinvar	8 clinvar	195 clinvar	16 clinvar		222
nonsense	6 clinvar	7 clinvar	2 clinvar			15
start loss						0
frameshift	7 clinvar	5 clinvar				12
splice donor/acceptor (+/-2bp)	2 clinvar	6 clinvar	3 clinvar			11
Total	18	26	207	84	0	335

Highest pathogenic variant AF is 0.00009298197

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182943.3	RefSeq	NP_891988.1	20	MANE Select
ENST00000282903.10	Ensembl	ENSP00000282903.5	20	MANE Select
NM_000935.3	RefSeq	NP_000926.2	19	Standard
ENST00000360060.7	Ensembl	ENSP00000353170.3	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
plod2	Danio rerio	Structure: bone tissue Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

plod2

Danio rerio

Structure: bone tissue

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Pathways in clear cell renal cell carcinoma
Collagen biosynthesis and modifying enzymes
Collagen formation
Extracellular matrix organization

Biological Process

response to hypoxia
cellular protein modification process
protein O-linked glycosylation
peptidyl-lysine hydroxylation
collagen fibril organization

Molecular Function

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

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
rough endoplasmic reticulum membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000282903
Coding exons: 20
Length: 94214
Individuals with no LoFs: 125653
Homozygous LoFs: 0
Heterozygous LoFs: 91
Defined: 125744
p: 0.000362

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.561	369	401	0.921	0.0000199	5010
Missense (PolyPhen)		113	127.03	0.88958		1571
Synonymous	-0.432	142	136	1.05	0.00000654	1369
Loss of Function	3.51	20	45.6	0.439	0.00000246	543

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.0019	0.0019	notable
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.00026	0.00026	rare
Other	0.00033	0.00033	rare

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: Note=PLOD2 mutations give rise to a broad variety of phenotypes with variable degrees of severity of bone fragility and joint contractures. Disease-associated mutations have been found in patients with autosomal recessive osteogenesis imperfecta (AR- OI) (PubMed:22689593). {ECO:0000269|PubMed:22689593}.;

Recessive Scores

pRec: 0.128

Intolerance Scores

LoFtool: 0.185
RVIS EVS: 0.11
RVIS percentile EVS: 62.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.666

Gene Damage Prediction

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