Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000507846 | SCV000603116 | pathogenic | not provided | 2017-09-14 | criteria provided, single submitter | clinical testing | The p.Gly256Val variant alters a glycine in triple helix repeat domain of COL1A2 and the majority of osteogenesis imperfecta (OI) associated collagen variants occur at a glycine residue within this region. The p.Gly256Val variant has been reported twice in literature in association with OI type IV (Pollitt 2006 and Marini 2007).The p.Gly256Val variant absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Exome Aggregation Consortium (ExAC) browser. Altogether, the p.Gly256Val variant has been classified as pathogenic |
| Invitae | RCV002231188 | SCV000627355 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2023-07-26 | criteria provided, single submitter | clinical testing | 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). 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. ClinVar contains an entry for this variant (Variation ID: 439504). This missense change has been observed in individuals with osteogenesis imperfecta type IV (PMID: 16786509, 17078022). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 256 of the COL1A2 protein (p.Gly256Val). |
| Gene |
RCV000507846 | SCV001783080 | pathogenic | not provided | 2021-12-16 | criteria provided, single submitter | clinical testing | Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-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 (Stenson et al, 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17078022, 16786509) |
| Genomics England Pilot Project, |
RCV001542469 | SCV001760202 | likely pathogenic | Osteogenesis imperfecta, perinatal lethal | no assertion criteria provided | clinical testing |