Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002235563 | SCV000961888 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2024-01-02 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 631 of the COL1A2 protein (p.Gly631Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 27509835). ClinVar contains an entry for this variant (Variation ID: 663292). 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. |
| 3billion | RCV001809838 | SCV002059137 | pathogenic | Osteogenesis imperfecta with normal sclerae, dominant form | 2022-01-03 | criteria provided, single submitter | clinical testing | The variant has been observed in at least two similarly affected unrelated individuals (PMID: 27509835, PS4_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (PMID: source: PMID_17078022, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.976, 3CNET: 0.989, PP3_P). A missense variant is a common mechanism associated with Osteogenesis imperfecta (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |