Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001959021 | SCV002245363 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2021-12-29 | criteria provided, single submitter | clinical testing | 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. 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 variant is also known as p.Gly121Asp. This missense change has been observed in individual(s) with autosomal dominant osteogenesis imperfecta (PMID: 8829649, 22589248). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 211 of the COL1A2 protein (p.Gly211Asp). |
Prevention |
RCV003418259 | SCV004109735 | pathogenic | COL1A2-related disorder | 2023-04-17 | criteria provided, single submitter | clinical testing | The COL1A2 c.632G>A variant is predicted to result in the amino acid substitution p.Gly211Asp. The p.Gly211 amino acid is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Marini et al. 2007. PubMed ID: 17078022). This variant was reported in at least two individuals with osteogenesis imperfecta (reported as Gly121 in Table 4, Zhuang et al. 1996. PubMed ID: 8829649; Table S1, Chen et al. 2022. PubMed ID: 35154279). In addition, a different variant affecting the same amino acid (Gly211Val) was reported in one individual with osteogenesis imperfecta (Bardai. 2017. PubMed ID: 28378289). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. |