ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.796G>C (p.Gly266Arg) (rs1555574493)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000558433 SCV000627282 likely pathogenic Osteogenesis imperfecta type I 2017-05-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 266 of the COL1A1 protein (p.Gly266Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL1A1-related disease. 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). A different missense substitution at this codon (p.Gly288Glu) has been reported in an individual affected with osteogenesis imperfecta (PMID: 15728585). This suggests that the glycine residue is critical for COL1A1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a novel missense change affecting a residue that is known to be critical for normal protein structure, stability and function. This type of missense change is also highly enriched in affected individuals and expected to be pathogenic. However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.

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