Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002231244 | SCV000627346 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2024-01-01 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 130 of the COL1A2 protein (p.Gly130Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features consistent with autosomal dominant osteogenesis imperfecta (PMID: 17078022, 24342908; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 456836). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. |
Athena Diagnostics | RCV000991603 | SCV001143200 | pathogenic | not provided | 2019-08-07 | criteria provided, single submitter | clinical testing | The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and not found in general population data. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. |
Gene |
RCV000991603 | SCV001823955 | pathogenic | not provided | 2022-12-19 | criteria provided, single submitter | clinical testing | Identified in patients with osteogenesis imperfecta referred for genetic testing at GeneDx and in published literature (Marini et al., 2007); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 (HGMD); This variant is associated with the following publications: (PMID: 25525159, 24342908, 35163361, 17078022) |
Revvity Omics, |
RCV000991603 | SCV002017440 | pathogenic | not provided | 2021-06-03 | criteria provided, single submitter | clinical testing |