Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000200200 | SCV000249838 | likely pathogenic | not provided | 2024-08-14 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Functional in vitro studies on patient-derived fibroblasts showed a reduction in type V protein expression (PMID: 22696272); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22696272, 34265140) |
| Labcorp Genetics |
RCV002229055 | SCV000814178 | pathogenic | Ehlers-Danlos syndrome, classic type, 1 | 2022-06-04 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1492 of the COL5A1 protein (p.Gly1492Ser). This missense change has been observed in individuals with Ehlers-Danlos syndrome or its clinical features (PMID: 22696272; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 212981). 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 expected to disrupt COL5A1 protein function. Studies have shown that this missense change alters COL5A1 gene expression (PMID: 22696272). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the triple helix domain of COL5A1. 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 variants at these glycine residues in COL5A1 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. For these reasons, this variant has been classified as Pathogenic. |