Clinical and Molecular Spectrum Associated with COL6A3 c.7447A>G p.(Lys2483Glu) Variant: Elucidating its Role in Collagen VI-related Myopathies

Rocío N. Villar-Quiles, Sandra Donkervoort, Alix De Becdelièvre, Corine Gartioux, Valérie Jobic, A. Reghan Foley, Riley M. McCarty, Ying Hu, Rita Menassa, Laurence Michel, Gaelle Gousse, Arnaud Lacour, Philippe Petiot, Nathalie Streichenberger, Ariane Choumert, Leá Declerck, J. A. Urtizberea, Guilhem Sole, Alain Furby, Matthieu CérinoMartin Krahn, Emmanuelle Campana- Salort, Ana Ferreiro, Bruno Eymard, Carsten G. Bönnemann, Diana Bharucha-Goebel, Charlotte J. Sumner, Anne M. Connolly, Pascale Richard, Valérie Allamand, Corinne Métay, Tanya Stojkovic

Research output: Contribution to journalArticlepeer-review


Background: Dominant and recessive autosomal pathogenic variants in the three major genes (COL6A1-A2-A3) encoding the extracellular matrix protein collagen VI underlie a group of myopathies ranging from early-onset severe conditions (Ullrich congenital muscular dystrophy) to milder forms maintaining independent ambulation (Bethlem myopathy). Diagnosis is based on the combination of clinical presentation, muscle MRI, muscle biopsy, analysis of collagen VI secretion, and COL6A1-A2-A3 genetic analysis, the interpretation of which can be challenging. Objective: To refine the phenotypical spectrum associated with the frequent COL6A3 missense variant c.7447A>G (p.Lys2483Glu). Methods: We report the clinical and molecular findings in 16 patients: 12 patients carrying this variant in compound heterozygosity with another COL6A3 variant, and four homozygous patients. Results: Patients carrying this variant in compound heterozygosity with a truncating COL6A3 variant exhibit a phenotype consistent with COL6-related myopathies (COL6-RM), with joint contractures, proximal weakness and skin abnormalities. All remain ambulant in adulthood and only three have mild respiratory involvement. Most show typical muscle MRI findings. In five patients, reduced collagen VI secretion was observed in skin fibroblasts cultures. All tested parents were unaffected heterozygous carriers. Conversely, two out of four homozygous patients did not present with the classical COL6-RM clinical and imaging findings. Collagen VI immunolabelling on cultured fibroblasts revealed rather normal secretion in one and reduced secretion in another. Muscle biopsy from one homozygous patient showed myofibrillar disorganization and rimmed vacuoles. Conclusions: In light of our results, we postulate that the COL6A3 variant c.7447A>G may act as a modulator of the clinical phenotype. Thus, in patients with a typical COL6-RM phenotype, a second variant must be thoroughly searched for, while for patients with atypical phenotypes further investigations should be conducted to exclude alternative causes. This works expands the clinical and molecular spectrum of COLVI-related myopathies.

Original languageEnglish
Pages (from-to)633-645
Number of pages13
JournalJournal of Neuromuscular Diseases
Issue number4
Publication statusPublished - 2021

Subject classification (UKÄ)

  • Medical Genetics
  • Neurology


  • COL6A3
  • collagen type VI
  • Collagen VI-related myopathies
  • congenital muscular dystrophy (CMD)
  • limb-girdle muscular dystrophy (LGMD)
  • muscular MRI
  • neuromuscular disorders
  • NGS


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