Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255945 | SCV000322640 | pathogenic | not provided | 2016-08-30 | criteria provided, single submitter | clinical testing | The pathogenic G876E variant in the COL5A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G876E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G876E 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. The G876E variant affects a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G876E as a pathogenic variant. |
| Invitae | RCV002229730 | SCV000830553 | uncertain significance | Ehlers-Danlos syndrome, classic type, 1 | 2018-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with glutamic acid at codon 876 of the COL5A2 protein (p.Gly876Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and missense variants at these glycine residues in COL5A2 are more frequently observed in individuals with disease than in the general population (PMID: 22696272, 23587214). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. In summary, this variant is a novel missense change affecting a residue that is critical for protein structure, stability and function. However, the available evidence is currently insufficient to determine its role 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 COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 265645). |