Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002234410 | SCV000752615 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2022-09-10 | 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: 526895). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 8829649, 22206639, 22589248, 26627451, 27519266). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 460 of the COL1A2 protein (p.Gly460Ser). |
Blueprint Genetics | RCV001597190 | SCV001832515 | pathogenic | not provided | 2020-03-13 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV001597190 | SCV002017434 | pathogenic | not provided | 2020-05-29 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001597190 | SCV002499975 | pathogenic | not provided | 2022-04-11 | criteria provided, single submitter | clinical testing | Variant 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, which is an established mechanism of disease.; Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22589248, 29620724, 19344236, 15241796, 22206639, 7695699, 8218237, 9016532, 17078022, 26627451, 27519266, 32335877, 34007986, 30266093, 32123938, 33939306, 33942288, 8829649) |
3billion | RCV003313968 | SCV004013695 | pathogenic | Osteogenesis imperfecta, perinatal lethal | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000526895 / PMID: 8829649 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |