ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.3040C>T (p.Arg1014Cys) (rs72653170)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763407 SCV000894136 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 RCV000420639 SCV000516589 pathogenic not provided 2018-06-11 criteria provided, single submitter clinical testing The R1014C variant in the COL1A1 gene has been reported previously, sometimes using alternate nomenclature (as R836C), in multiple individuals with Caffey disease (Gensure et al., 2005; Ranganath et al., 2011). Skin biopsy from an affected adult with the R1014C variant demonstrated less densely packed collagen fibrils of variable shape and size surrounded by granular material, while analysis of collagen fibrils in cultured skin fibroblasts indicated increased disulfide crosslinking (Gensure et al., 2005). The R1014C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R1014C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1014C as a pathogenic variant.
GeneReviews RCV000018889 SCV000054466 pathologic Infantile cortical hyperostosis 2012-08-02 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000685879 SCV000813379 pathogenic Osteogenesis imperfecta type I 2018-05-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1014 of the COL1A1 protein (p.Arg1014Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs72653170, ExAC 0.01%). This variant has been reported to segregate with Caffey disease in several families (PMID: 15864348, 21567126, 18704262) and has been reported as a common change in many individuals with Caffey disease (PMID: 21249479, 24390061, 18704262, 18553566, 17309652). The variant is also known as p.Arg836Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 17347). Experimental studies have shown that this missense change produced abnormal disulfide-bonded dimeric α1(I) chains in skin fibroblast cultures and was associated with abnormal collagen fibril architecture (PMID: 15864348). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018889 SCV000039173 pathogenic Infantile cortical hyperostosis 2008-07-15 no assertion criteria provided literature only

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