Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000018729 | SCV005835155 | uncertain significance | Ehlers-Danlos syndrome, classic type, 1 | 2024-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1489 of the COL5A1 protein (p.Gly1489Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome (PMID: 10602121, 10946364; internal data). This variant is also known as G1489D. ClinVar contains an entry for this variant (Variation ID: 17189). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL5A1 protein function with a positive predictive value of 80%. 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. This variant disrupts the p.Gly1489 amino acid residue in COL5A1. Other variant(s) that disrupt this residue have been observed in individuals with COL5A1-related conditions (PMID: 19370768), which suggests that this may be a clinically significant amino acid residue. 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. |
| OMIM | RCV000018729 | SCV000039012 | pathogenic | Ehlers-Danlos syndrome, classic type, 1 | 2000-08-14 | no assertion criteria provided | literature only |