Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000433178 | SCV000536430 | uncertain significance | not provided | 2018-11-24 | criteria provided, single submitter | clinical testing | The P947T variant of uncertain significance in the COL5A2 gene has not been published as pathogenic or been reported as benign to our knowledge. P947T is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P947T 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. Moreover, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, P947T does not affect 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). However, in contrast to several other collagen genes, relatively few pathogenic Glycine substitutions have been reported in COL5A2 in association with EDS. Most pathogenic variants in COL5A2 are in-frame splice site changes that cause exon skipping (Symoens et al., 2012). |
| Invitae | RCV002230298 | SCV001515279 | uncertain significance | Ehlers-Danlos syndrome, classic type, 1 | 2023-05-23 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 947 of the COL5A2 protein (p.Pro947Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 393071). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL5A2 protein function. 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. |