Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414112 | SCV000491656 | likely pathogenic | not provided | 2016-11-07 | criteria provided, single submitter | clinical testing | The G844A variant in the COL1A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G844A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G844A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, the G844A variant results in substitution for glycine within the triple helical domain and occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby residues (G841S, G844D, G847R) have been reported in the Human Gene Mutation Database in association with osteogenesis imperfecta (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G844A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Invitae | RCV002230748 | SCV001207415 | likely pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2023-02-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 844 of the COL1A2 protein (p.Gly844Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of COL1A2-related condition (Invitae). ClinVar contains an entry for this variant (Variation ID: 373093). 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. 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 disrupts the p.Gly844 amino acid residue in COL1A2. Other variant(s) that disrupt this residue have been observed in individuals with COL1A2-related conditions (PMID: 26627451), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |