Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002241076 | SCV001381754 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2022-10-17 | criteria provided, single submitter | clinical testing | This variant disrupts the triple helix domain of COL1A2. 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, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 916 of the COL1A2 protein (p.Gly916Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of osteogenesis imperfecta (PMID: 22206639, 25835785). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 940648). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL1A2 protein function. For these reasons, this variant has been classified as Pathogenic. |