ClinVar Genomic variation as it relates to human health

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); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7691343, 19637253, 17078022, 29807018, 24486247, 29620724, 18996919)

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 7695699, 8218237, 19344236). 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: VCV000647159). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

For these reasons, this variant has been classified as Pathogenic. 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). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 425 of the COL1A1 protein (p.Gly425Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 7691343, 17078022, 18996919, 19637253, 24486247). ClinVar contains an entry for this variant (Variation ID: 647159). 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 COL1A1 protein function. This missense change is located within a functionally conserved triple helix domain of the COL1A1 protein and variants that affect the glycine residue in Gly-Xaa-Yaa repeats of the collagen triple helix are known to disrupt protein folding and stability (PMID: 8218237, 7695699).