COL6A1
protein-codingcollagen type VI alpha 1 chain, the group of Collagens
Gene summary
The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~23.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0009681
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0100225
Submitter: ClinGen
*COL6A1*, encoding Collagen Type VI Alpha 1, is one of several genes encoding the major structural protein Collagen VI. The protein's basic structural unit is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains additionally encoded by the genes *COL6A2* and *COL6A3* to form the triple helical structural element common to collagens. Mutations in Collagen VI have historically been reported in relation to two different conditions. The first, Ullrich congenital muscular dystrophy, was first described in a series of papers in the 1930s by Otto Ullrich and was notable due to occurrence of both weakness and joint hypermobility (Kongenitale atonisch-sklerotische Muskeldystrophie, 1930) and was classically considered a recessive condition. The second, Bethlem myopathy, was reported by Bethlem and van Wijngaarden in 1976 as a dominant myopathy with development of joint contractures (PMID: 963533). Genetic analysis in patients with each of these disorders revealed both dominant and recessive defects in one of the *COL6A1*, *COL6A2*, or *COL6A3* genes that affect the final Collagen VI protein. On the basis of clinical as well as genetic findings, Ullrich CMD and Bethlem myopathy can justifiably be regarded as being positioned at the flanking ends of a continuous spectrum of disease, rather than as distinct clinical entities (PMID: 21496625). As such *COL6A1* was curated in relation to a combined disease entity: collagen 6-related Myopathy. Collagen 6-related Myopathy illustrates the important role that collagen VI has in skeletal muscle. In addition to progressive muscle weakness and wasting, patients have skin and tendon abnormalities that reflect a more generalized connective tissue disorder. Dominant and recessive variants are found in patients across the clinical disease spectrum of collagen 6-related Myopathy. Distinct variants are associated with dominant and recessive inheritance and have been curated separately by the Congenital Myopathies GCEP. Dominant inheritance occurs with dominant negative mutations in the collagen VI triple helical regions, including glycine substitution and exon skip mutations. In contrast, recessive inheritance occurs with loss of function variants. More than 100 unique variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting the relationship between *COL6A1* and autosomal dominant collagen 6-related myopathy includes case-level data, segregation data, and experimental data. Variants included in this curation have been reported in at least 18 probands in five publications (PMIDs: 12840783, 16130093, 15563506, 17785673, 20976770). Many other cases are available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease association is additionally supported by several pieces of experimental evidence, including its interaction with additional disease-causing genes *COL6A2* and *COL6A3* (PMID: 7768905), its function in the basement membrane surrounding muscle fibers (PMID: 9334230), which is disrupted in patient cells (PMID: 18825676) with altered expression in the extracellular matrix (PMID: 15563506). There are several animal models, including a col6a1 zebrafish knockdown which strongly recapitulates disease (PMID: 20338942) as well as additional mouse (PMIDs: 9817932, 28043812) and canine (PMID: 26438297) models supporting the role of *COL6A* in congenital myopathy. In summary, *COL6A1* is definitively associated with autosomal dominant collagen 6-related myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0008029
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0000355
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0100225
Submitter: ClinGen
*COL6A1*, encoding Collagen Type VI Alpha 1, is one of several genes encoding the major structural protein Collagen VI. The protein's basic structural unit is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains additionally encoded by the genes *COL6A2* and *COL6A3* to form the triple helical structural element common to collagens. Mutations in Collagen VI have historically been reported in relation to two different conditions. The first, Ullrich congenital muscular dystrophy, was first described in a series of papers in the 1930s by Otto Ullrich and was notable due to occurrence of both weakness and joint hypermobility (Kongenitale atonisch-sklerotische Muskeldystrophie, 1930) and was classically considered a recessive condition. The second, Bethlem myopathy, was reported by Bethlem and van Wijngaarden in 1976 as a dominant myopathy with development of joint contractures (PMID: 963533). Genetic analysis in patients with each of these disorders revealed both dominant and recessive defects in one of the *COL6A1*, *COL6A2*, or *COL6A3* genes that affect the final Collagen VI protein. On the basis of clinical as well as genetic findings, Ullrich CMD and Bethlem myopathy can justifiably be regarded as being positioned at the flanking ends of a continuous spectrum of disease, rather than as distinct clinical entities (PMID: 21496625). As such *COL6A1* was curated in relation to a combined disease entity: collagen 6-related Myopathy. Collagen 6-related Myopathy illustrates the important role that collagen VI has in skeletal muscle. In addition to progressive muscle weakness and wasting, patients have skin and tendon abnormalities that reflect a more generalized connective tissue disorder. Dominant and recessive variants are found in patients across the clinical disease spectrum of collagen 6-related Myopathy. Distinct variants are associated with dominant and recessive inheritance and have been curated separately by the Congenital Myopathies GCEP. Dominant inheritance occurs with dominant negative mutations in the collagen VI triple helical regions, including glycine substitution and exon skip mutations. In contrast, recessive inheritance occurs with loss of function variants. More than 100 unique variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting the relationship between *COL6A1* and autosomal recessive collagen 6-related myopathy includes case-level data, segregation data, and experimental data. Variants included in this curation have been reported in at least 10 probands in five publications (PMIDs: 16130093, 20976770, 23738969, 15689448, 24271325). Many other cases are available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease association is additionally supported by several pieces of experimental evidence, including its interaction with additional disease-causing genes *COL6A2* and *COL6A3* (PMID: 7768905), its function in the basement membrane surrounding muscle fibers (PMID: 9334230), which is disrupted in Col6a1–/– cells (PMID: 23743995) with altered expression in the extracellular matrix (PMID: 12297580). There are several animal models, including mouse (PMIDs: 9817932, 28043812) and canine (PMID: 26438297) models supporting the role of *COL6A1* in congenital myopathy. In summary, *COL6A1* is definitively associated with autosomal recessive collagen 6-related myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0024530
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009681
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009681
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0009681
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0024530
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0024530
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COL6A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001848.3. 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 | 3 | 1 | 25 | 324 | 26 | 379 |
| missense | 27 | 45 | 404 | 289 | 44 | 809 |
| nonsense | 12 | 4 | 4 | 20 | ||
| start loss | 2 | 2 | ||||
| frameshift | 27 | 13 | 6 | 46 | ||
| splice donor/acceptor (+/-2bp) | 37 | 38 | 26 | 101 | ||
| Total | 106 | 101 | 467 | 613 | 70 | 1357 |
Highest pathogenic variant AF is 0.000033632707
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001839.2 | 35 | MANE Select | |
| Ensembl | ENSP00000355180.3 | 35 | MANE Select | |
| Ensembl | ENSP00000483630.2 | 7 | Standard | |
| Ensembl | ENSP00000507333.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| col6a1 | Danio rerio | Structure: skeletal muscle cell Quality: structure abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- ECM-receptor interaction - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- Protein digestion and absorption - Homo sapiens (human)
- Human papillomavirus infection - Homo sapiens (human)
Biological Process
- osteoblast differentiation
- growth plate cartilage chondrocyte morphogenesis
- cell adhesion
- extracellular matrix organization
- endodermal cell differentiation
Molecular Function
- extracellular matrix structural constituent conferring tensile strength
- platelet-derived growth factor binding
Cellular Component
- extracellular region
- collagen type VI trimer
- extracellular space
- lysosomal membrane
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361866
- Coding exons
- 35
- Length
- 23314
- Individuals with no LoFs
- 125710
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 33
- Defined
- 125743
- p
- 0.000131
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.501 | 644 | 681 | 0.946 | 0.0000494 | 6530 |
| Missense (PolyPhen) | 213 | 219.05 | 0.97237 | 2037 | ||
| Synonymous | -1.42 | 343 | 311 | 1.10 | 0.0000276 | 2074 |
| Loss of Function | 6.45 | 8 | 63.5 | 0.126 | 0.00000346 | 706 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00015 | 0.00014 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Collagen VI acts as a cell-binding protein.;
- Disease
- DISEASE: Bethlem myopathy 1 (BTHLM1) [MIM:158810]: A benign proximal myopathy characterized by early childhood onset and joint contractures most frequently affecting the elbows and ankles. {ECO:0000269|PubMed:11865138, ECO:0000269|PubMed:15689448, ECO:0000269|PubMed:15955946, ECO:0000269|PubMed:8782832}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ullrich congenital muscular dystrophy 1 (UCMD1) [MIM:254090]: A congenital myopathy characterized by muscle weakness and multiple joint contractures, generally noted at birth or early infancy. The clinical course is more severe than in Bethlem myopathy. {ECO:0000269|PubMed:15689448, ECO:0000269|PubMed:16130093, ECO:0000269|PubMed:17785674}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.540
Intolerance Scores
- LoFtool
- 0.0443
- RVIS EVS
- -1.49
- RVIS percentile EVS
- 3.62
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.676
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | High | Medium | High |
| Cancer | High | High | High |