Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000087474 | SCV001229839 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2019-02-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with arginine at codon 411 of the COL3A1 protein (p.Gly411Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. 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. This variant has been observed in an individual affected with Ehlers-Danlos syndrome, vascular type (PMID: 24922459). ClinVar contains an entry for this variant (Variation ID: 101237). This variant is not present in population databases (ExAC no frequency). |
| Ambry Genetics | RCV002362738 | SCV002666663 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-01-14 | criteria provided, single submitter | clinical testing | The p.G411R variant (also known as c.1231G>C), located in coding exon 18 of the COL3A1 gene, results from a G to C substitution at nucleotide position 1231. The glycine at codon 411 is replaced by arginine, an amino acid with dissimilar properties. The majority (approximately two-thirds) of COL3A1 mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64). This particular glycine substitution has been reported in an individual with a type B aortic dissection and a diagnosis of vascular Ehlers-Danlos syndrome (vEDS) (Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Shalhub S et al. J Vasc Surg, 2019 11;70:1543-1554). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif in the COL3A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Collagen Diagnostic Laboratory, |
RCV000087474 | SCV000120361 | pathogenic | Ehlers-Danlos syndrome, type 4 | no assertion criteria provided | clinical testing |