Submissions for variant NM_000089.4(COL1A2):c.874G>C (p.Gly292Arg)

dbSNP: rs906553840

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523423	SCV000620111	pathogenic	not provided	2017-08-14	criteria provided, single submitter	clinical testing	The G292R variant in the COL1A2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The G292R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G292R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and is within the Gly-X-Y triple helical region. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby residues (G286V/A, G289V/A, G292S/D, G295V) have been reported in the Human Gene Mutation Database in association with osteogenesis imperfecta (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G292R as a pathogenic variant.
Invitae	RCV001858003	SCV002157395	pathogenic	Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1	2022-11-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly292 amino acid residue in COL1A2. Other variant(s) that disrupt this residue have been observed in individuals with COL1A2-related conditions (PMID: 24296239, 26177859; Invitae), which suggests that this may be a clinically significant amino acid residue. 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: 451413). This missense change has been observed in individual(s) with clinical features of osteogenesis imperfecta (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 292 of the COL1A2 protein (p.Gly292Arg).