Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000018763 | SCV001394447 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2022-08-20 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly666 amino acid residue in COL3A1. Other variant(s) that disrupt this residue have been observed in individuals with COL3A1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. This variant disrupts the triple helix domain of COL3A1. 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). In COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). 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 COL3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17223). This variant is also known as G499D. This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome, vascular type (PMID: 8664902, 10706896). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 666 of the COL3A1 protein (p.Gly666Asp). |
| OMIM | RCV000018763 | SCV000039046 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2000-03-09 | no assertion criteria provided | literature only | |
| Collagen Diagnostic Laboratory, |
RCV000018763 | SCV000120263 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |