ClinVar Miner

Submissions for variant NM_000088.4(COL1A1):c.1732G>A (p.Gly578Ser)

dbSNP: rs1907330109
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001054858 SCV001219214 likely pathogenic Osteogenesis imperfecta type I 2019-02-15 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 578 of the COL1A1 protein (p.Gly578Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333).. 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003117728 SCV003800621 likely pathogenic Osteogenesis imperfecta 2023-01-08 criteria provided, single submitter clinical testing Variant summary: COL1A1 c.1732G>A (p.Gly578Ser) results in a non-conservative amino acid change in a critical amino acid in the encoded protein sequence. Alterations of glycine residues within/near the collagen triple-helix in COL1A1 are common mechanisms of disease. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251380 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1732G>A in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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