ClinVar Miner

Submissions for variant NM_000089.3(COL1A2):c.298G>A (p.Gly100Ser) (rs1410254723)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GenomeConnect, ClinGen RCV000845036 SCV000986872 not provided Osteogenesis imperfecta type I no assertion provided phenotyping only Variant interpretted as Likely pathogenic and reported on 08/07/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000631535 SCV000752617 likely pathogenic Ehlers-Danlos syndrome, classic type; Osteogenesis imperfecta type I 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 100 of the COL1A2 protein (p.Gly100Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL1A2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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, 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.

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