COL1A1
protein-codingcollagen type I alpha 1 chain, the group of Collagens
Gene summary
This gene encodes the pro-alpha1 chains 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 VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0030854
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007244
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007522
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007244
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100599
Submitter: ClinGen
*COL1A1* was first reported in relation to AD *COL1A1*-related Ehlers-Danlos syndrome in 1986 (Cole et al., PMID: 3082886). *COL1A1*-related Ehlers-Danlos syndrome is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility, with or without congenital hip dislocation, extreme joint laxity, and osteogenesis imperfecta. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities (Ehlers-Danlos syndrome, classic type, 1, MIM: 130000; Ehlers-Danlos syndrome, arthrochalasia type, 1, MIM: 130060; Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, MIM:619115) have been lumped into one disease entity, *COL1A1*-related Ehlers-Danlos syndrome. The split curations for Caffey disease and osteogenesis imperfecta have been curated separately. 8 missense, 3 splicing, and one indel variants that have been reported in 18 probands in 4 publications (PMIDs: 3082886, 15728585, 32091183, 34265140) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be due to interference with N-propeptide removal or alteration of the N-proteinase cleavage site necessary for proper collagen processing (PMIDs: 23692737, 18409203). This gene-disease association is also supported by experimental evidence including a mouse model, three expression studies, two biochemical function studies, and functional alteration in patient cells (PMIDs: 24443344, 6519194, 28206959, 19669491, 16407265, 19233756, 18409203). In summary, there is definitive evidence supporting the relationship between *COL1A1* and *COL1A1*-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 October 3rd, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0019019
Submitter: ClinGen
*COL1A1* was first reported in relation to AD osteogenesis imperfecta in 1986 (Cohn et al., PMID: 3016737). Osteogenesis imperfecta is a disorder of connective tissues characterized by increased susceptibility to bone fractures and decreased bone density. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities (osteogenesis imperfecta, type I, MIM:166200; osteogenesis imperfecta, type II, MIM:166210; osteogenesis imperfecta, type III, MIM:259420; osteogenesis imperfecta, type IV, MIM:166220) have been lumped into one disease entity, osteogenesis imperfecta. The split curations for Caffey disease and *COL1A1*-related Ehlers-Danlos syndrome have been curated separately. 11 missense, 4 frameshift, 3 splicing, 1 nonsense variants that have been reported in 19 probands in 6 publications (PMIDs: 3016737, 7942841, 25633413, 35113812, 17078022, 31653500) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is reported to be haploinsufficiency or dominant negative. This gene-disease association is also supported by experimental evidence including three mouse models, three expression studies, and a biochemical function study (PMIDs: 10608859, 2450280, 24443344, 6519194, 28206959, 19669491, 16407265). In summary, there is definitive evidence supporting the relationship between *COL1A1* and AD 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 June 6th, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0007244
Submitter: ClinGen
*COL1A1* was first reported in relation to autosomal dominant Caffey Disease in 2005 (Gensure et al., PMID: 15864348). Caffey disease is characterized by an infantile episode of massive subperiosteal new bone formation that typically involves the diaphyses of the long bones, mandible, and clavicles. Painful swelling and systemic fever often accompany the episode, which usually begins before the age of 5 months and resolves before age 2 years. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, *COL1A1*-related osteogenesis imperfecta (types I-IV, OMIM:166200, OMIM:166210, OMIM:259420, OMIM:166220), *COL1A1*-related Ehlers-Danlos syndrome (lumped Ehlers-Danlos Syndrome, arthrochalasia type, 1 (OMIM:130060), combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 (OMIM:619115), Ehlers-Danlos Syndrome, classic type, 1 (not associated with *COL1A1* in OMIM)), and Caffey disease (OMIM:114000). The split curations have been curated separately. Two variants (c.3040C>T; p.Arg1014Cys and c.2752C>T; p.Arg918Cys) that have been reported in 40 probands in 7 publications (PMIDs: 15864348, 17309652, 18704262, 21249479, 21567126, 24390061, 34272483) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (11.9/12 pts.) has been reached. *COL1A1*-related Caffey disease is most frequently caused by the c.3040C>T (p.Arg1014Cys) variant (previously known as p.Arg836Cys), believed to disrupt specific type I collagen-ligand interaction (PMID: 24389367). This gene-disease association is also supported by expression throughout the skeletal system and functional alteration in patient cells (PMIDs: 15864348, 19669491, 34272483). In summary, *COL1A1* is definitively associated with autosomal dominant Caffey Disease. 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 11/2/2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0007522
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008148
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017791
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008148
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0009804
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008147
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007244
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007525
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007525
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008146
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007525
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009804
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007244
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007525
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Dermatologic; Musculoskeletal; Obstetric; Ophthalmologic
Intervention: Cardiovascular; Obstetric
Rationale: Individuals with Ehlers-Danlos syndrome, classic type, 1; ay have aortic root dilatation (as well as arterial/vascular fragility), but the natural history is unclear, and many not commonly progress, though yearly surveillance with echocardiogram when aortic dilatation or mitral valve prolapse is peresent has been recommended; Precautions in pregnancy may be beneficial; In Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, cardiovascular manifestations such as aortic root dilatation have been described, and awareness may allow surveillance and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COL1A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000088.4. 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 | 1 | 2 | 24 | 544 | 17 | 588 |
| missense | 244 | 292 | 676 | 231 | 14 | 1457 |
| nonsense | 125 | 28 | 1 | 154 | ||
| start loss | 7 | 7 | ||||
| frameshift | 452 | 118 | 1 | 571 | ||
| splice donor/acceptor (+/-2bp) | 204 | 76 | 31 | 311 | ||
| Total | 1033 | 516 | 733 | 775 | 31 | 3088 |
Highest pathogenic variant AF is 0.0000316
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000079.2 | 51 | MANE Select | |
| Ensembl | ENSP00000225964.6 | 51 | MANE Select | |
| Ensembl | ENSP00000460459.1 | 4 | Standard | |
| Ensembl | ENSP00000531392.1 | 31 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| col1a1a | Danio rerio | Structure: osteoblast Quality: increased size 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
- ossification
- blood vessel development
- osteoblast differentiation
- intramembranous ossification
Molecular Function
- protease binding
- extracellular matrix structural constituent
- protein binding
- extracellular matrix structural constituent conferring tensile strength
- identical protein binding
Cellular Component
- extracellular region
- collagen type I trimer
- extracellular space
- cytoplasm
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000225964
- Coding exons
- 51
- Length
- 18344
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125748
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.53 | 600 | 898 | 0.668 | 0.0000568 | 9116 |
| Missense (PolyPhen) | 20 | 52.573 | 0.38042 | 494 | ||
| Synonymous | -1.00 | 353 | 330 | 1.07 | 0.0000227 | 3284 |
| Loss of Function | 8.23 | 4 | 86.8 | 0.0461 | 0.00000512 | 938 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000030 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000028 | 0.000026 | rare |
| South Asian | 0.000033 | 0.000033 | 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: Caffey disease (CAFFD) [MIM:114000]: Characterized by an infantile episode of massive subperiosteal new bone formation that typically involves the diaphyses of the long bones, mandible, and clavicles. The involved bones may also appear inflamed, with painful swelling and systemic fever often accompanying the illness. The bone changes usually begin before 5 months of age and resolve before 2 years of age. {ECO:0000269|PubMed:15864348}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ehlers-Danlos syndrome, classic type, 1 (EDSCL1) [MIM:130000]: A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. The main features of classic Ehlers-Danlos syndrome are joint hypermobility and dislocation, and fragile, bruisable skin. EDSCL1 inheritance is autosomal dominant. {ECO:0000269|PubMed:10739762, ECO:0000269|PubMed:17211858}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Ehlers-Danlos syndrome, arthrochalasia type, 1 (EDSARTH1) [MIM:130060]: A form of Ehlers-Danlos syndrome, a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDSARTH1 is an autosomal dominant form characterized by frequent congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement. {ECO:0000269|PubMed:18409203, ECO:0000269|PubMed:9295084}. 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:1634225, ECO:0000269|PubMed:16638323, ECO:0000269|PubMed:16705691, ECO:0000269|PubMed:16786509, ECO:0000269|PubMed:1718984, ECO:0000269|PubMed:1737847, ECO:0000269|PubMed:17875077, ECO:0000269|PubMed:18670065, ECO:0000269|PubMed:24682174, ECO:0000269|PubMed:2794057, ECO:0000269|PubMed:3244312, ECO:0000269|PubMed:8223589}. 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:1460047, ECO:0000269|PubMed:1511982, ECO:0000269|PubMed:1613761, ECO:0000269|PubMed:16566045, ECO:0000269|PubMed:16786509, ECO:0000269|PubMed:18670065, ECO:0000269|PubMed:1874719, ECO:0000269|PubMed:18996919, ECO:0000269|PubMed:1939261, ECO:0000269|PubMed:1953667, ECO:0000269|PubMed:2035536, ECO:0000269|PubMed:2036375, ECO:0000269|PubMed:2037280, ECO:0000269|PubMed:2116413, ECO:0000269|PubMed:2211725, ECO:0000269|PubMed:2339700, ECO:0000269|PubMed:2470760, ECO:0000269|PubMed:25958000, ECO:0000269|PubMed:2777764, ECO:0000269|PubMed:2794057, ECO:0000269|PubMed:2913053, ECO:0000269|PubMed:3016737, ECO:0000269|PubMed:3108247, ECO:0000269|PubMed:3403550, ECO:0000269|PubMed:3667599, ECO:0000269|PubMed:7520724, ECO:0000269|PubMed:7679635, ECO:0000269|PubMed:7691343, ECO:0000269|PubMed:7961597, ECO:0000269|PubMed:8100209, ECO:0000269|PubMed:8349697, ECO:0000269|PubMed:8349698, ECO:0000269|PubMed:8364588, ECO:0000269|PubMed:8456808, ECO:0000269|PubMed:8786074, ECO:0000269|PubMed:9143923, ECO:0000269|Ref.49, ECO:0000269|Ref.52}. 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:16879195, ECO:0000269|PubMed:1770532, ECO:0000269|PubMed:18670065, ECO:0000269|PubMed:2037280, ECO:0000269|PubMed:2511192, ECO:0000269|PubMed:2794057, ECO:0000269|PubMed:7691343, ECO:0000269|PubMed:7881420, ECO:0000269|PubMed:8019571, ECO:0000269|PubMed:8364588, ECO:0000269|PubMed:8456809, ECO:0000269|PubMed:8669434, ECO:0000269|PubMed:8723681, ECO:0000269|PubMed:9101304}. 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:16786509, ECO:0000269|PubMed:16879195, ECO:0000269|PubMed:1770532, ECO:0000269|PubMed:17875077, ECO:0000269|PubMed:1988452, ECO:0000269|PubMed:2745420, ECO:0000269|PubMed:7691343, ECO:0000269|PubMed:7982948, ECO:0000269|PubMed:8094076, ECO:0000269|PubMed:8339541, ECO:0000269|PubMed:9600458}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteoporosis (OSTEOP) [MIM:166710]: A systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. {ECO:0000269|PubMed:8841196, ECO:0000269|PubMed:9535665}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving COL1A1 is found in dermatofibrosarcoma protuberans. Translocation t(17;22)(q22;q13) with PDGF.;
Recessive Scores
- pRec
- 0.991
Intolerance Scores
- LoFtool
- 0.00406
- RVIS EVS
- -1.79
- RVIS percentile EVS
- 2.26
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.955
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |