COL1A2
protein-codingcollagen type I alpha 2 chain, the group of Collagens
Gene summary
This gene encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]
- OI4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~36.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009159
Submitter: ClinGen
*COL1A2* was first reported in relation to autosomal recessive Ehlers-Danlos syndrome, cardiac valvular type in 1987 (Shohet et al., PMID: 2952379). Ehlers-Danlos syndrome, cardiac valvular type is a connective tissue disorder primarily affecting the skin, joints, and blood vessel walls. This syndrome is typically characterized by the presence of joint hypermobility, soft hyperextensibility, easy bruisability, and atrophic scar formation with the presence of cardiac valvular defects comprising mitral and/or aortic valve insufficiency. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, *COL1A2*-related osteogenesis imperfecta (types I-IV OMIM:166210, OMIM:259420, OMIM:166220), *COL1A2*-related Ehlers-Danlos syndrome (arthrochalasia type and combined osteogenesis imperfecta and Ehlers Danlos syndrome OMIM:617821, OMIM:619120), and *COL1A2*-related Ehlers-Danlos syndrome, cardiac valvular type (OMIM:225320). The split curations have been curated separately. Five variants (nonsense and splice site) that have been reported in 5 probands in three publications (PMIDs: 30821104, 16816023, 15077201) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, *COL1A2* is definitively associated with autosomal recessive Ehlers-Danlos syndrome, cardiac valvular type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date 12/5/22 (SOP Version 9).
Inheritance Pattern: Unknown
Disease ID:MONDO:0005453
Submitter: ClinGen
*COL1A2* was first reported in relation to congenital heart disease in 2017 (Jin et al., PMID: 28991257). This gene-disease relationship in the literature reports both autosomal dominant and recessive cases, so the mode of inheritance is currently undetermined. Four unique variants (1 homozygous missense, 3 heterozygous missense) that have been reported in four probands with CHD in three publications are included in this curation (PMID: 28991257, 33064175, 35885997). However, these variants were not scored due to a high minor allele frequency in gnomAD v.4 or a low REVEL score. This gene-disease relationship is supported by expression data in mouse cardiac tissues (PMID: 18816857). In summary, the evidence supporting the relationship between *COL1A2* and congenital heart disease has been disputed, and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *COL1A2* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date September 9th, 2024 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0040501
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0008148
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008147
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0030855
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100596
Submitter: ClinGen
*COL1A2* was first reported in relation to autosomal dominant *COL1A2*-related osteogenesis imperfecta in 1988 (Wenstrup et al., PMID: 2897363). *COL1A2* has been noted to be associated with multiple disease entities. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been split and assesed separately, Ehlers-Danlos syndrome and Ehlers-Danlos syndrome, cardiac valvular type. Based on overlap in phenotypic spectrums and shared modes of inheritance, osteogenesis imperfecta types 1, 2, 3, and 4 were lumped under a single disese entity, *COL1A2*-related osteogenesis imperfecta. This curation addresses *COL1A2* in relation to osteogenesis inperfecta. Evidence supporting this gene-disease relationship includes case-level and experimental data. At least 18 unique variants (missense, splice-site, frameshift, duplication, and small deletion) that have been reported in 20 probands in 11 publications (PMIDs: 2897363, 8257992, 11836364, 18375391, 8081394, 34306033, 1301191, 22795120, 9923651,19594296, 35052464) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Variants in this gene segregated with disease in 6 additional family members (PMIDs: 18375391). This gene-disease relationship is also supported by functional assay, protein interaction, and animal models (PMIDs: 8786074, 32482890, 19594296, 8446583, 30579604). In summary, there is definitive evidence to support the relationship between *COL1A2* and autosomal dominant *COL1A2*-related osteogenesis Imperfecta. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date December 5th, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0040501
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0016470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017791
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009159
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019019
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009159
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0100606
Submitter: ClinGen
*COL1A2* was first reported in relation to autosomal dominant *COL1A2*-related Ehlers-Danlos Syndrome in 1985 (Eyre et al., PMID:2993307). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities, Ehlers-Danlos syndrome, arthrochalasia type and combined osteogenesis inperfecta-Ehlers-Danlos syndrome have been lumped into a single disease entity, *COL1A2*-related Ehlers-Danlos syndrome. The *COL1A2*-related Ehlers-Danlos syndrome, cardiac valvular type was split separately due to autosomal recessive inheritance and a distinct mechanism. Notably, *COL1A2* has also been associated with osteogenesis inperfecta which has been curated separately. At least 12 unique variants (missense, splice-site) that have been reported in 19 probands across 9 publications (PMIDs: 2454224, 1712342, 1577745, 1556139, 9295084, 10982177, 23692737, 24440294, 32091183) are included in this curation. The mechanism of pathogenicity is known to be loss of function. Variants seen typically cause skipping of exon 6, eliminating the N-proteinase cleavage site necessary for proper collagen processing. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by expression studies (PMIDs: 1577745, 1556139). In summary, there is definitive evidence to support the relationship between *COL1A2* and autosomal dominant *COL1A2*-related Ehlers-Danlos Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date November 2nd, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0008147
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0040501
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009804
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009159
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007525
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008146
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0007525
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009804
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Dermatologic; Musculoskeletal; Ophthalmologic
Intervention: Cardiovascular
Rationale: Ehlers-Danlos syndrome, cardiac valvular form may be difficult to recognize, and cardiac manifestations, which can include arrhythmias may benefit from early (including surgical) interventions; Some individuals may also have arterial/vascular fragility, and awareness may allow appropriate precautions and prompt management of sequelae; In In Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, cardiovascular manifestations (eg, aortic dilatation, vascular fragility) have been described, and awareness may allow surveillance and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COL1A2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000089.4. 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 | 2 | 2 | 24 | 455 | 4 | 487 |
| missense | 303 | 277 | 735 | 47 | 2 | 1364 |
| nonsense | 10 | 4 | 5 | 19 | ||
| start loss | 1 | 1 | ||||
| frameshift | 24 | 15 | 2 | 41 | ||
| splice donor/acceptor (+/-2bp) | 42 | 37 | 29 | 108 | ||
| Total | 381 | 335 | 796 | 502 | 6 | 2020 |
Highest pathogenic variant AF is 0.000049575203
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000080.2 | 52 | MANE Select | |
| Ensembl | ENSP00000297268.6 | 52 | MANE Select | |
| Ensembl | ENSP00000629436.1 | 52 | Standard | |
| Ensembl | ENSP00000629437.1 | 52 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| col1a2 | Danio rerio | Structure: vertebra Quality: deformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Platelet activation - Homo sapiens (human)
- ECM-receptor interaction - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- Relaxin signaling pathway - Homo sapiens (human)
Biological Process
- skeletal system development
- blood vessel development
- transforming growth factor beta receptor signaling pathway
- Rho protein signal transduction
- blood coagulation
Molecular Function
- protease binding
- extracellular matrix structural constituent
- protein binding
- extracellular matrix structural constituent conferring tensile strength
- protein binding, bridging
Cellular Component
- extracellular region
- collagen type I trimer
- extracellular space
- endoplasmic reticulum
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000297268
- Coding exons
- 52
- Length
- 36672
- Individuals with no LoFs
- 125700
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 47
- Defined
- 125748
- p
- 0.000191
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.15 | 641 | 813 | 0.788 | 0.0000474 | 8521 |
| Missense (PolyPhen) | 32 | 62.385 | 0.51294 | 621 | ||
| Synonymous | -1.44 | 297 | 267 | 1.11 | 0.0000160 | 3088 |
| Loss of Function | 7.22 | 9 | 77.6 | 0.116 | 0.00000401 | 939 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000083 | 0.000079 | rare |
| South Asian | 0.00088 | 0.00085 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Type I collagen is a member of group I collagen (fibrillar forming collagen).;
- Disease
- DISEASE: Ehlers-Danlos syndrome, arthrochalasia type, 2 (EDSARTH2) [MIM:617821]: A form of Ehlers-Danlos syndrome, a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDSARTH2 is an autosomal dominant condition characterized by frequent congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement. {ECO:0000269|PubMed:1577745, ECO:0000269|PubMed:2394758, ECO:0000269|PubMed:3680255}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteogenesis imperfecta 1 (OI1) [MIM:166200]: An autosomal dominant 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. OI1 is a non-deforming form with normal height or mild short stature, and no dentinogenesis imperfecta. {ECO:0000269|PubMed:16705691, ECO:0000269|PubMed:16786509, ECO:0000269|PubMed:1990009, ECO:0000269|PubMed:8456807, ECO:0000269|PubMed:8829649}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteogenesis imperfecta 2 (OI2) [MIM:166210]: An autosomal dominant 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. OI2 is characterized by bone fragility, with many perinatal fractures, severe bowing of long bones, undermineralization, and death in the perinatal period due to respiratory insufficiency. {ECO:0000269|PubMed:10627137, ECO:0000269|PubMed:1284475, ECO:0000269|PubMed:1339453, ECO:0000269|PubMed:1385413, ECO:0000269|PubMed:16786509, ECO:0000269|PubMed:16879195, ECO:0000269|PubMed:1874719, ECO:0000269|PubMed:18996919, ECO:0000269|PubMed:2777764, ECO:0000269|PubMed:2914942, ECO:0000269|PubMed:7693712, ECO:0000269|PubMed:7891382, ECO:0000269|PubMed:7906591, ECO:0000269|PubMed:7959683, ECO:0000269|PubMed:8182080, ECO:0000269|Ref.34}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ehlers-Danlos syndrome, cardiac valvular type (EDSCV) [MIM:225320]: A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSCV is an autosomal recessive disease characterized by mitral valve prolapse and insufficiency, mitral regurgitation, and aortic insufficiency, in addition to joint laxity, skin hyperextensibility and friability, and abnormal scar formation. {ECO:0000269|PubMed:16816023}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteogenesis imperfecta 3 (OI3) [MIM:259420]: An autosomal dominant 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. OI3 is characterized by progressively deforming bones, very short stature, a triangular face, severe scoliosis, grayish sclera and dentinogenesis imperfecta. {ECO:0000269|PubMed:10408781, ECO:0000269|PubMed:16786509, ECO:0000269|PubMed:16879195, ECO:0000269|PubMed:1990009, ECO:0000269|PubMed:7520724, ECO:0000269|PubMed:7720740, ECO:0000269|PubMed:7749416, ECO:0000269|PubMed:7860070, ECO:0000269|PubMed:7881420, ECO:0000269|PubMed:8081394, ECO:0000269|PubMed:8444468, ECO:0000269|PubMed:8456807, ECO:0000269|PubMed:8723681, ECO:0000269|PubMed:8800927, ECO:0000269|PubMed:8829649}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteogenesis imperfecta 4 (OI4) [MIM:166220]: An autosomal dominant 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. OI4 is characterized by moderately short stature, mild to moderate scoliosis, grayish or white sclera and dentinogenesis imperfecta. {ECO:0000269|PubMed:1642148, ECO:0000269|PubMed:16786509, ECO:0000269|PubMed:16879195, ECO:0000269|PubMed:2052622, ECO:0000269|PubMed:2064612, ECO:0000269|PubMed:2897363, ECO:0000269|PubMed:7693712, ECO:0000269|PubMed:8094076, ECO:0000269|PubMed:8401517, ECO:0000269|PubMed:8800927}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving COL1A2 may be a cause of lipoblastomas, which are benign tumors resulting from transformation of adipocytes, usually diagnosed in children. Translocation t(7;8)(p22;q13) with PLAG1.;
Intolerance Scores
- LoFtool
- 0.00710
- RVIS EVS
- -1.14
- RVIS percentile EVS
- 6.36
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.170
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |