Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000531290 | SCV000631664 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2017-04-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Several different missense substitutions at this codon (p.Gly1167Arg, p.Gly1167Val, p.Gly1167Cys) are absent from population databases and have been observed in individuals with Ehlers-Danlos syndrome type IV (PMID: 24650746, 8680408, 24399159). This suggests that the glycine residue is critical for COL3A1 protein function and that other missense substitutions at this position may also be pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL3A1-related disease. This sequence change replaces glycine with aspartic acid at codon 1167 of the COL3A1 protein (p.Gly1167Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. 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). |
| Color Diagnostics, |
RCV001190483 | SCV001357983 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-01-03 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with aspartic acid at codon 1167 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein that are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it is expected to have deleterious impact on protein structure and function. This variant has been observed in an individual affected with Ehlers-Danlos syndrome (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. |