Homozygous splice variant (c.1741-6G>A) of the COL6A1 gene in three patients with Ullrich congenital muscular dystrophy.

• An intronic variant in the COL6A1 gene causes Ullrich congenital muscular dystrophy. • The variant was found in homozygosity in three patients originating from Turkey. • The variant led to aberrant splicing and loss-of-function of the COL6A1 transcript. • The variant has wrongly been classified as "likely benign" in Clinvar. • The variant led to impaired collagen VI secretion into the extracellular matrix. The three major collagen VI genes: COL6A1, COL6A2 , and COL6A3 encode microfibrillar components of extracellular matrices in multiple tissues including muscles and tendons. Pathogenic variants in the collagen VI genes cause collagen VI-related dystrophies representing a continuum of conditions from Bethlem myopathy at the milder end to Ullrich congenital muscular dystrophy at the more severe end. Here we describe a pathogenic variant in the COL6A1 gene (NM_001848.3; c.1741-6G>A) found in homozygosity in three patients with Ullrich congenital muscular dystrophy. The patients suffered from severe muscle impairment characterised by proximal weakness, distal hyperlaxity, joint contractures, wheelchair-dependency, and use of nocturnal non-invasive ventilation. The pathogenicity was verified by RNA analyses showing that the variant induced aberrant splicing leading to a frameshift and loss of function. The analyses were in line with immunocytochemistry studies of patient-derived skin fibroblasts and muscle tissue demonstrating impaired secretion of collagen VI into the extracellular matrix. Thereby, we add the variant c.1741-6G>A to the list of pathogenic, recessive, splice variants in COL6A1 causing Ullrich congenital muscular dystrophy. The variant is listed in ClinVar as of "uncertain significance" and "likely benign" and may presumably have been overlooked in other patients. [ABSTRACT FROM AUTHOR]