Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002242821 | SCV001582999 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2020-07-16 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 286 of the COL1A2 protein (p.Gly286Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant has been observed in individual(s) with osteogenesis imperfecta (PMID: 11317364). This variant is also known as G196A in the literature. 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). |
Molecular Genetics, |
RCV002225133 | SCV002503871 | likely pathogenic | Osteogenesis imperfecta | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace glycine with alanine at codon 286 of the COL1A2 protein, p.(Gly286Ala). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in a Gly-X-Y triplet repeat in the collagen alpha 1 chain triple helical domain. There is a moderate physicochemical difference between glycine and alanine. The variant is absent in a large population cohort (gnomAD v2.1), and has been identified in a case diagnosed with osteogenesis imperfecta type IV (PMID: 11317364). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). A different missense change at this amino acid residue (p.Gly286Ser) has been determined to be likely pathogenic (PMID: 25944380). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM2, PM5, PP3. |