Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001046767 | SCV001210681 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2020-01-30 | 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. 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). 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 not been reported in the literature in individuals with COL3A1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 750 of the COL3A1 protein (p.Gly750Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. |
| Color Diagnostics, |
RCV001179183 | SCV001343794 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-10-14 | criteria provided, single submitter | clinical testing | This missense variant replaces a conserved glycine with arginine at codon 750 in the triple helical region of the COL3A1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Because this variant alters a conserved glycine residue in the triple helical region of the protein, there is a suspicion that this variant may be associated with disease. However, additional studies are necessary to determine the role of this variant in disease conclusively. |