ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.1103G>C (p.Gly368Ala) (rs1555574151)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000538665 SCV000627163 likely pathogenic Osteogenesis imperfecta type I 2017-09-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 368 of the COL1A1 protein (p.Gly368Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. 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. 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). In addition, a different missense substitution at this codon (p.Gly368Ser) has been determined to be pathogenic (PMID: 17078022, 27519266, 24668929), further suggesting that this variant is deleterious. In summary, this variant is a novel missense change affecting a residue crucial for protein structure and stability. Although additional genetic data will be necessary to further confirm pathogenicity for this variant, glycine substitutions located in COL1A1 triple helix domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic.

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