Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001219405 | SCV001391341 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2019-05-02 | criteria provided, single submitter | clinical testing | 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). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). This variant has been observed in an individual with clinical features of COL3A1-related conditions (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 378 of the COL3A1 protein (p.Gly378Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. |