ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.634G>A (p.Gly212Arg)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003050488 SCV003442500 pathogenic Osteogenesis imperfecta type I 2022-06-04 criteria provided, single submitter clinical testing This variant is also known as Gly34Arg. This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 15728585, 27509835). 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 212 of the COL1A1 protein (p.Gly212Arg). 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 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 variant disrupts the p.Gly212 amino acid residue in COL1A1. Other variant(s) that disrupt this residue have been observed in individuals with COL1A1-related conditions (PMID: 21667357, 31414283), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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