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 occurence of both weakness and joint hypermobility (Kongenitale atonisch-sklerotische Muskeldystrophie, 1930). 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. As these disorders are clearly on a clinical spectrum of phenotypic severity (PMID: 21496625), COL6A1 was curated in relation to a combined disease entity: Semidominant Collagen 6-Related Myopathy. Almost 200 unique variants (e.g. missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar and HGMD. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.

Variants in this gene have been reported in at least nine probands in four publications (PMIDs: 8782832, 12840783, 16130093, 23738969). These include a variety of dominant negative glycine substitutions that interrupt the Gly-X-Y sequences in the triple helical domain, in-frame deletions in the same region, and premature termination variants that lead to a complete loss-of-function among others. The gene segregated with the disease in many other family members in the original families characterized by Bethlem, yielding a combined LOD score of 6.21. 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. Loss of Collagen VI's function as a structural protein, including binding components of the ECM and indirect regulation of processes such as autophagy (PMID: 21037586) and muscle stiffness/satellite cell renewal (PMID: 23743995), perfectly matches the hyperlaxity and muscle-related phenotypes observed in the myopathy, as does primary expression in the skeletal muscle. Functional evidence in Collagen VI Null mice confirming the impact of Collagen VI on autophagy and muscle stiffness/satellite cell renewal, with restoration of these functions rescuing some amount of the phenotypes, also helps explain the pathogenic mechanism. Finally, the alteration of COL6A1 in two models, a hypomorphic mouse model and canines with a natural homozygous termination codon (Glu98Ter), recapitulates the myopathy phenotype observed in humans.

In summary, COL6A1 is definitively associated with semidominant collagen 6-related myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.