ClinVar

Description

The p.G304S variant (also known as c.910G>A), located in coding exon 18 of the COL1A2 gene, results from a G to A substitution at nucleotide position 910. The glycine at codon 304 is replaced by serine, an amino acid with similar properties, and is located in the triple helical domain. The majority of pathogenic mutations identified to date in COL1A2 have involved the substitution of another amino acid for glycine within the triple-helical domain (Dagleish R. Nucleic Acids Res. 1997 Jan 1;25(1):181-7; Marini JC et al. Hum Mutat. 2007 Mar;28(3):209-21; Bardai G et al. Osteoporos Int 2016 Dec;27(12):3607-3613). This particular glycine substitution has been detected in a cohort of patients with reported well-defined clinical diagnoses of osteogenisis imperfecta (OI), where this variant was indicated as associated with feaures of OI type I as well as possible overlapping features of Ehlers-Danlos syndrome; however, clinical details were limited (Maioli M et al. Eur J Hum Genet, 2019 07;27:1090-1100). In another study, this variant was detected in an additional proband who was also reported to have features of OI type I (Kaux JF et al. Rev Med Liege. 2009 Jan;64(1):11-5). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif in the COL1A2 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.