Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000522149 | SCV000619275 | uncertain significance | not provided | 2017-07-26 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the COL1A2 gene. The R440C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R440C 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). The R440C 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. Additionally, 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. Missense variants in nearby residues (G439D, G442E, G445R) have been reported in the Human Gene Mutation Database in association with osteogenesis imperfecta (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Center for Human Genetics, |
RCV000659376 | SCV000781187 | uncertain significance | Connective tissue disorder | 2016-11-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002231636 | SCV001507115 | uncertain significance | Osteogenesis imperfecta type I; Ehlers-Danlos syndrome, classic type, 1 | 2020-06-27 | criteria provided, single submitter | clinical testing | 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. 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. This variant has not been reported in the literature in individuals with COL1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 450667). This variant is present in population databases (rs754825427, ExAC 0.003%). This sequence change replaces arginine with cysteine at codon 440 of the COL1A2 protein (p.Arg440Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. |