Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Neuberg Centre For Genomic Medicine, |
RCV001823557 | SCV002073077 | likely pathogenic | Osteogenesis imperfecta type I | criteria provided, single submitter | clinical testing | The missense variant p.G197V in COL1A1 (NM_000088.4) has not been reported previously in affected patients. A different variant affecting the amino acid residue has been reported to be disease causing (Lindahl K et al,2015). The p.G197V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Missense changes affecting the glycine residue have been reported to be disease causing. The p.G197V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 197 of COL1A1 is conserved in all mammalian species. The nucleotide c.590 in COL1A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. | |
Ce |
RCV002264392 | SCV002545951 | pathogenic | not provided | 2022-05-01 | criteria provided, single submitter | clinical testing | COL1A1: PS1, PS2, PM2, PP3, PS4:Supporting |
Labcorp Genetics |
RCV001823557 | SCV004509503 | pathogenic | Osteogenesis imperfecta type I | 2023-01-02 | criteria provided, single submitter | clinical testing | This variant disrupts the triple helix domain of COL1A1. 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 COL1A1, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 1339103). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 30715774). 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 197 of the COL1A1 protein (p.Gly197Val). For these reasons, this variant has been classified as Pathogenic. |