ClinVar Miner

Submissions for variant NM_000088.3(COL1A1):c.3680G>A (p.Arg1227His) (rs543809032)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489075 SCV000577031 uncertain significance not specified 2017-04-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL1A1 gene. The R1227H variant has not been published as pathogenic or been reported as benign to our knowledge. The R1227H 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. Nevertheless, the R1227H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with osteogenesis imperfecta (Stenson et al., 2014). Additionally, R1227H is not located in a Gly-X-Y motif in the triple helical region of the COL1A1 gene, where the majority of pathogenic missense variants affect a triplet Glycine and result in osteogenesis imperfecta (Stenson et al., 2014).
Invitae RCV000526752 SCV000627248 uncertain significance Osteogenesis imperfecta type I 2017-03-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1227 of the COL1A1 protein (p.Arg1227His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs543809032, ExAC 0.01%) but has not been reported in the literature in individuals with a COL1A1-related disease. This variant has been observed in a heterozygous individual unaffected by COL1A1 related conditions (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.