ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.994G>A (p.Gly332Arg) (rs72645357)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Medical Sciences,Uppsala University RCV000490676 SCV000574644 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763413 SCV000894142 pathogenic Osteogenesis imperfecta with normal sclerae, dominant form; Postmenopausal osteoporosis; Osteogenesis imperfecta, recessive perinatal lethal; Osteogenesis imperfecta type III; Infantile cortical hyperostosis; Ehlers-Danlos syndrome, procollagen proteinase deficient; Osteogenesis imperfecta type I 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000480634 SCV000567265 pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing The G332R variant in the COL1A1 gene has been reported previously in two unrelated individuals with aprogressive deforming type of osteogenesis imperfecta (type III) and was reported as G154R due to the useof alternate nomenclature (Pruchno et al., 1991). The G332R substitution was notobserved in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The G332R variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silicoanalysis predicts this variant is probably damaging to the protein structure/function. In addition, missensevariants in nearby residues (G323R, G323E, G326D, G338S, G338C) have been reported in the HumanGene Mutation Database in association with osteogenesis imperfecta (Stenson et al., 2014), supporting thefunctional importance of this region of the protein. We interpret G332R as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000029586 SCV000052238 pathogenic Osteogenesis imperfecta 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000692051 SCV000819858 pathogenic Osteogenesis imperfecta type I 2018-03-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 332 of the COL1A1 protein (p.Gly332Arg). 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 been reported to segregate with disease in a family (PMID: 8669434) and in individuals affected with osteogenesis imperfecta (PMID: 17078022, 25086671, 22589248, 2037280, 26177859). This variant has been reported as novo in at least two individuals (PMID: 26177859), and is also known as p.Gly154Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 17312). 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). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018853 SCV000039136 pathogenic Osteogenesis imperfecta type III 1996-01-11 no assertion criteria provided literature only

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