Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414693 | SCV000491173 | pathogenic | not provided | 2017-07-26 | criteria provided, single submitter | clinical testing | The G196C variant in the COL1A2 gene has been reported previously in an individual with osteogenesis imperfecta type IV (Zhang et al., 2011). The G196C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G196C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, affecting a Glycine residue in the Gly-X-Y repetitive motif of the triple helical region of the COL1A2 gene. In this domain, the Glycine in the triplet repeat is critical for protein folding and substitution of a triplet Glycine is a known pathogenic mechanism (Steiner et al., 2013). In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, other missense variants at this same residue (G196D, G196V) and missense variants affecting nearby Glycine residues (G190V, G193S, G193D) have been reported in the Human Gene Mutation Database in association with COL1A2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G196C as a pathogenic variant. |
| Invitae | RCV001861415 | SCV002243454 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2021-09-10 | 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). ClinVar contains an entry for this variant (Variation ID: 372734). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 21667357). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 196 of the COL1A2 protein (p.Gly196Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. |