Submission Details

COL6A3 was first reported in relation to autosomal dominant Bethlam myopathy in 1998 (Pan et al., PMID: 9536084). Since then, the disease has been associated with autosomal recessive and dominant forms of Bethlem myopathy, Ulrich congenital muscular dystrophy, and dystonia. Per criteria outlined by the ClinGen Lumping and Splitting Working group and the clinical and genetic findings of patients, we found Bethlem myopathy (OMIM:158810) and Ulrich congenital muscular dystrophy (OMIM:254090) to lie on ends of a clinical spectrum and lumped these entities into Collagen VI-related dystrophy. The split curation for autosomal recessive dystonia will be assessed separately. Fourteen variants (missense, nonsense, splicing) that have been reported in 5 publications (PMIDs: 9536084, 9536084, 11992252, 15689448, 24038877) are included in this curation. At least one variant in this gene segregated with disease in 10 additional family members. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by animal models, protein interactions, expression studies, and assays demonstrating functional alterations in both patient and non-patient cells (PMIDs: 11707460, 18825676, 20729548, 6307276, 18366090, 24563484, 23564457). In summary, there is definitive evidence to support the relationship between COL6A3 and autosomal dominant/autosomal recessive collagen VI-related dystrophy. 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 Myopathy GCEP on the meeting date 5/24/21 (SOP Version 8).