Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000695723 | SCV000824238 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2018-06-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with arginine at codon 1038 of the COL3A1 protein (p.Gly1038Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. A different missense substitution at this codon (p.Gly1038Asp) has been observed in an individual with Ehlers-Danlos syndrome (PMID: 25758994). 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, missense variants at 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. This variant has not been reported in the literature in individuals with COL3A1-related disease. This variant is not present in population databases (ExAC no frequency). |
| ARUP Laboratories, |
RCV000755957 | SCV000883642 | pathogenic | not provided | 2017-07-30 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV000695723 | SCV004842576 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2023-12-15 | criteria provided, single submitter | clinical testing | This variant, a glycine substitution within the Gly-Xaa-Yaa repeats of the triple helical domain of COL3A1, results in a deleterious effect to the protein that is sufficient to be disease-causing. Glycine, the smallest amino acid, is required to form the stable triple helical domain, and substitution by an amino acid with a bulkier side chain will interfere with folding and secretion of the molecule (PMID: 24922459, 25758994). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described. Substitution of the triplet glycine is the most common mutational mechanism for vascular EDS (PMID: 7695699, 8218237, 19344236). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. |