ClinVar Genomic variation as it relates to human health

This variant results in the substitution of a glycine residue in a Gly-X-Y motif in the triple helix region. Glycine changes in these regions are reported to be damaging to protein function (PMID 17078022). This variant has been identified in multiple individuals with clinical features associated with this gene (PMID: 16705691, 16879195, 17078022, 21667357, 21884818, 22753364, 26627451). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 257 of the COL1A1 protein (p.Gly257Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 8613526, 21667357, 22206639, 23692737, 26627451). This variant is also known as 888G>A (helical codon 79 Gly to Arg). ClinVar contains an entry for this variant (Variation ID: 425639). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Osteogenesis imperfect types I-IV, and other conditions (OMIM). Variants resulting in a truncated protein are known to have a loss of function effect on protein, while missense variants affecting the G-X-Y of a triple helix motif, have a dominant negative effect (PMIDs:27509835, 12362985). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Interfamilial variability is apparent among individuals with the same OI type and intrafamilial variability is apparent among individuals with the same causative variant (Genereviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional Gly-X-Y motif. Variants that disrupt the glycine of the Gly-X-Y motif are known to product structural defects in the collagen molecule (PMID: 12362985). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Gly257Glu) variant has been observed in an individual with COL1A1-related disease by a clinical laboratory in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with osteogenesis imperfecta. The majority of these individuals had osteogenesis imperfecta type I (MIM#166200) (ClinVar, PMIDs). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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 (PMID: 34007986); 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; Also known as c.888G>A; This variant is associated with the following publications: (PMID: 37334733, 37270749, 35154279, 30614853, 32166892, 33939306, 25525159, 22206639, 30886339, 30477250, 31447884, 32314604, 21667357, 23692737, 26627451, 32123938, 32786180, 35822426, 28626166, 34007986, 36709916, 36964972, 35909573, 37432431, 8613526)

ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PP3 supporting

The COL1A1 c.769G>A variant is predicted to result in the amino acid substitution p.Gly257Arg. This variant has been repeatedly reported to be causative for osteogenesis imperfecta (see example: reported as p.Gly79Arg, Redford-Badwal et al. 1996. PubMed ID: 8613526; Additional file 1, Swinnen et al. 2011. PubMed ID: 22206639; Zhang et al. 2012. PubMed ID: 21667357; Table 1, Malfait et al. 2013. PubMed ID: 23692737; Table 1, Lin et al. 2015. PubMed ID: 26627451). The p.Gly79 amino acid is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Marini et al. 2007. PubMed ID: 17078022). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.