ClinVar

Description

In summary, this variant is a novel missense change affecting a residue that is known to be critical for normal protein structure, stability and function. This type of missense change is also highly enriched in affected individuals and expected to be pathogenic. However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL1A1, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). Different missense substitutions at this codon (p.Gly269Ser and p.Gly269Val ) have been reported in individuals affected with osteogenesis imperfecta (PMID: 17078022). This suggests that the glycine residue is critical for COL1A1 protein function and that other missense substitutions at this position may also be pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 269 of the COL1A1 protein (p.Gly269Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine.