Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002234320 | SCV000937990 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2018-07-25 | criteria provided, single submitter | clinical testing | 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. The observation of one or more missense substitutions at this codon (p.Gly448Glu) in affected individuals suggests that this may be a clinically significant residue (PMID: 17078022). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with COL1A2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 448 of the COL1A2 protein (p.Gly448Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. |
| Baylor Genetics | RCV000850502 | SCV000992704 | likely pathogenic | Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, cardiac valvular type; Ehlers-danlos syndrome, arthrochalasia type, 2 | 2018-10-12 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV003238813 | SCV003936309 | pathogenic | not provided | 2022-12-28 | criteria provided, single submitter | clinical testing | Occurs in the triple helical domain and replaces the glycine in the canonical GlyX-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (Jovanovic et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34007986, 31216405) |