Variants in the COL6A1, COL6A2, and COL6A3 Genes in Collagen VI-related Congenital Muscular Dystrophy (P2.042)

OBJECTIVE: To determine the frequencies and distributions of mutations and variants of unknown clinical significance (VUS) in the COL6A1 , COL6A2 , and COL6A3 genes in specimens analyzed for collagen VI-related congenital muscular dystrophy (CMD) at a clinical laboratory. BACKGROUND: Mutations in the COL6A1 , COL6A2 , and COL6A3 genes cause a mild to severe clinical continuum of disorders including Bethlem myopathy (BM), Ullrich congenital muscular dystrophy (UCMD), and intermediate phenotypes. The genotype/phenotype correlation is challenging due to the high degree of clinical and genetic heterogeneity in patients with similar mutations occurring across the clinical spectrum. DESIGN/METHODS: Mutation analysis was performed by direct DNA sequencing of the entire coding regions of COL6A1 , COL6A2 , and COL6A3. The frequencies and distributions of pathogenic variants were calculated using de-identified test results from specimens (n=68) sent to a clinical laboratory for evaluation. RESULTS: Overall, 10 of the 68 specimens (15[percnt]) were positive for mutations in at least one of the three genes. The highest frequency of pathogenic variants was detected in COL6A1 (69[percnt], n=9), followed by COL6A3 (23[percnt], n=3) and COL6A2 (8[percnt], n=1). These mutations included glycine substitutions in the triple helical domain (46[percnt], n=6), splice site mutations (38[percnt], n=5), a small deletion (8[percnt], n=1), and a frameshift (8[percnt], n=1). Variants of unknown significance (VUS; n=75) were predominantly found in COL6A3 (55[percnt], n=41); 64[percnt] of the total VUS were non-synonymous (resulting in amino acid substitutions) and 44[percnt] were synonymous. CONCLUSIONS: In this large study, glycine substitutions (46[percnt] vs. 28[percnt]) and splice site mutations (38[percnt] vs. 28[percnt]) accounted for a larger proportion of pathogenic COL6A mutations than expected based on previous studies. We report that this set of genes is highly polymorphic, with a predominance of VUS in COL6A3 . Disclosure: Dr. Jaremko has received personal compensation for activities with Quest Diagnostics. Dr. Morneau has received personal compensation for activities with Quest Diagnostics. Dr. Smith has received personal compensation for activities with Quest Diagnostics. Dr. Wang has received personal compensation for activities with Quest Diagnostics. Dr. Suer has received personal compensation for activities with Quest Diagnostics. Dr. Hoffman has received personal compensation for activities with Quest Diagnostics. Dr. Liaquat has received personal compensation for activities with Quest Diagnostics. Dr. McCarthy has received personal compensation for activities with Quest Diagnostics. Dr. Lapierre has received personal compensation for activities with Quest Diagnostics. Dr. Storozuk has received personal compensation for activities with Quest Diagnostics. Dr. Meservey has received personal compensation for activities with Quest Diagnostics. Dr. Batish has received personal compensation for activities with Quest Diagnostics. Dr. Higgins has received personal compensation for activities with Quest Diagnostics.