Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002232871 | SCV000815896 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2018-04-12 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with serine at codon 841 of the COL1A2 protein (p.Gly841Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate in a family affected with severe, progressively deforming osteogenesis imperfecta  (PMID: 9099837). The variant is also known as p.Gly751Ser in the literature. Experimental studies have shown that this missense change affects the thermal stability of the collagen I and produces unstable collagen I (PMID: 9099837). 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 COL1A2, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. |