COL6A2
protein-codingcollagen type VI alpha 2 chain, the group of Collagens
Gene summary
This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [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 ~34.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009681
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0024530
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0100225
Submitter: ClinGen
COL6A2, encoding Collagen Type VI Alpha 2, 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 COL6A1 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, which also includes limb-girdle and myosclerosis phenotypes, rather than as distinct clinical entities (PMID: 21496625). As such COL6A2 was curated in relation to a combined disease entity: Collagen 6-Related Myopathy. This disorder 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 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; heterozygous carriers of COL6A2 premature stop variants have no obvious phenotype but patients with homozygous or compound heterozygous premature stop variants completely lack collagen VI and tend to have severe disease. More than 90 unique variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants included in this curation have been reported in at least 24 probands in 8 publications (PMIDs: 8618682, 11865138, 15563506, 18825676, 17785673, 20976770, 37023487, 25535305). 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 COL6A1 and COL6A3 (PMID: 7768905), its function in the basement membrane surrounding muscle fibers (PMID: 9334230), which is disrupted in patient cells with altered expression in the extracellular matrix (PMID: 15563506), and models in both mice (PMID: 28650483) and zebrafish (PMID: 26362255). In summary, COL6A2 is definitively associated with dominant collagen 6-related myopathy. 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 Congenital Myopathies Gene Curation Expert Panel on 6/27/2022 and by the ClinGen Limb Girdle Muscular Dystrophy Gene Curation Expert Panel (secondary contributor to this curation) on 11/09/2021 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0958235
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008029
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0009681
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009681
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009681
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0024530
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0100225
Submitter: ClinGen
COL6A2, encoding Collagen Type VI Alpha 2, 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 COL6A1 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, which also includes limb-girdle and myosclerosis phenotypes, rather than as distinct clinical entities (PMID: 21496625). As such COL6A2 was curated in relation to a combined disease entity: Collagen 6-Related Myopathy. This disorder 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 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; heterozygous carriers of COL6A2 premature stop variants have no obvious phenotype but patients with homozygous or compound heterozygous premature stop variants completely lack collagen VI and tend to have severe disease. More than 90 unique variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting the relationship between COL6A2 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 13 probands in 7 publications (PMIDs: 11381124, 15563506, 18852439, 19949035, 17785673, 37023487, 25535305). 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 COL6A1 and COL6A3 (PMID: 7768905), its function in the basement membrane surrounding muscle fibers (PMID: 9334230), which is disrupted in patient cells with altered expression in the extracellular matrix (PMID: 15563506), and models in both mice (PMID: 28650483) and zebrafish (PMID: 26362255). In summary, COL6A2 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. This classification was approved by the ClinGen Congenital Myopathies Gene Curation Expert Panel on 6/27/2022 and by the ClinGen Limb Girdle Muscular Dystrophy Gene Curation Expert Panel (secondary contributor to this curation) on 11/09/2021 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0000355
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009714
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0958235
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
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
Comments: Medical treatment (eg, with Cyclosporin A) may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COL6A2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001849.4. 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 | 27 | 437 | 11 | 477 | |
| missense | 24 | 68 | 720 | 187 | 8 | 1007 |
| nonsense | 25 | 13 | 2 | 40 | ||
| start loss | 1 | 1 | ||||
| frameshift | 39 | 29 | 5 | 73 | ||
| splice donor/acceptor (+/-2bp) | 45 | 46 | 24 | 2 | 117 | |
| Total | 133 | 158 | 779 | 626 | 19 | 1715 |
Highest pathogenic variant AF is 0.0000764335
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001840.3 | 27 | MANE Select | |
| Ensembl | ENSP00000300527.4 | 27 | MANE Select | |
| RefSeq | NP_478054.2 | 27 | MANE Plus Clinical | |
| RefSeq | NP_478055.2 | 27 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| col6a2 | Danio rerio | Structure: muscle cell Quality: undifferentiated 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
- growth plate cartilage chondrocyte morphogenesis
- cell adhesion
- response to glucose
- extracellular matrix organization
- protein heterotrimerization
Molecular Function
- protein binding
- extracellular matrix structural constituent conferring tensile strength
Cellular Component
- extracellular region
- collagen trimer
- extracellular space
- endoplasmic reticulum lumen
- extracellular matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000300527
- Coding exons
- 27
- Length
- 34753
- Individuals with no LoFs
- 125683
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 63
- Defined
- 125746
- p
- 0.000251
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.15 | 799 | 713 | 1.12 | 0.0000549 | 6538 |
| Missense (PolyPhen) | 320 | 334.25 | 0.95736 | 2843 | ||
| Synonymous | -6.61 | 463 | 314 | 1.47 | 0.0000288 | 2069 |
| Loss of Function | 4.06 | 22 | 54.3 | 0.405 | 0.00000284 | 601 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00045 | 0.00043 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.00050 | 0.00050 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00026 | 0.00025 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00049 | 0.00049 | rare |
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:17886299, 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:15563506, ECO:0000269|PubMed:15689448}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myosclerosis autosomal recessive (MYOSAR) [MIM:255600]: A condition characterized by chronic inflammation of skeletal muscle with hyperplasia of the interstitial connective tissue. The clinical picture includes slender muscles with firm 'woody' consistency and restriction of movement of many joints because of muscle contractures. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.379
Intolerance Scores
- LoFtool
- 0.0126
- RVIS EVS
- -1
- RVIS percentile EVS
- 8.22
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.399
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |