ClinVar Miner

Submissions for variant NM_000089.3(COL1A2):c.1342G>C (p.Gly448Arg)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000798375 SCV000937990 pathogenic Ehlers-Danlos syndrome, classic type; Osteogenesis imperfecta type I 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 448 of the COL1A2 protein (p.Gly448Arg). 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). 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). The observation of one or more missense substitutions at this codon (p.Gly448Glu) in affected individuals suggests that this may be a clinically significant residue (PMID: 17078022). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000850502 SCV000992704 likely pathogenic Osteogenesis imperfecta with normal sclerae, dominant form; Osteogenesis imperfecta, recessive perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, autosomal recessive, cardiac valvular form; EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2 2018-10-12 criteria provided, single submitter clinical testing

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