ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.4196G>A (p.Arg1399His) (rs146035171)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521165 SCV000618736 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing The R1399H variant of uncertain significance in the COL1A1 gene has not been published as pathogenic or been reported as benign to our knowledge. The R1399H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R1399H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, R1399H does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL1A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Fulgent Genetics,Fulgent Genetics RCV000765368 SCV000896633 uncertain significance 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
Invitae RCV000792484 SCV000931786 uncertain significance Osteogenesis imperfecta type I 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1399 of the COL1A1 protein (p.Arg1399His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs146035171, ExAC 0.02%). This variant has not been reported in the literature in individuals with COL1A1-related disease. ClinVar contains an entry for this variant (Variation ID: 450185). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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