ClinVar Miner

Submissions for variant NM_000089.3(COL1A2):c.1127G>T (p.Gly376Val) (rs67543427)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000702255 SCV000831102 pathogenic Ehlers-Danlos syndrome, classic type; Osteogenesis imperfecta type I 2018-06-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 376 of the COL1A2 protein (p.Gly376Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with osteogenesis imperfecta (OI) (Invitae) and has also been reported in an additional individual affected with OI, type IV (PMID: 17078022). 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). Variants that disrupt the p,Gly376 amino acid residue in COL1A2 have been observed in affected individuals (PMID: 17078022, 27509835, 9240878). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763175 SCV000893766 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, recessive perinatal lethal; Osteogenesis imperfecta type III; Ehlers-Danlos syndrome, autosomal recessive, cardiac valvular form; EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2 2018-10-31 criteria provided, single submitter clinical testing

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