Submission Details

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.