Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Mayo Clinic Laboratories, |
RCV001843974 | SCV002103212 | likely pathogenic | not provided | 2022-06-01 | criteria provided, single submitter | clinical testing | PP3, PM1, PM2_supporting, PS4_moderate |
Gene |
RCV001843974 | SCV002512897 | pathogenic | not provided | 2022-04-28 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain and replaces a glycine in a 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 (Jovanovic et al., 2021); This variant is associated with the following publications: (PMID: 17078022, 21239989, 31039433, 34007986, 9272740, 34025714, 18311573, 1634225) |
Genome Diagnostics Laboratory, |
RCV002276905 | SCV002565572 | likely pathogenic | Ehlers-Danlos syndrome | 2022-07-22 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV002543291 | SCV003516457 | pathogenic | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 901 of the COL1A2 protein (p.Gly901Ser). This variant is present in population databases (rs72659306, gnomAD 0.0009%). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 9272740, 17078022). This variant is also known as G811S. ClinVar contains an entry for this variant (Variation ID: 1343353). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. |