Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000222891 | SCV000271211 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2015-04-06 | criteria provided, single submitter | clinical testing | The p.Gly252Cys variant has not been previously reported in individuals with cli nical features of Ehlers-Danlos syndrome type IV (EDS IV) and it was absent from large population studies. However, other variants affecting the same residue ha ve been reported in more than 9 affected individuals (p.Gly252Arg, p.Gly252Asp, p.Gly252Val; Pepin 2000, Kerwin 2008, Muller 2011, Ferre 2011, Pepin 2014, Frank 2015). Computational prediction tools and conservation analysis suggest that th e p.Gly252Cys variant may impact the protein. Variants in COL3A1 affecting conse rved glycine (Gly) residues of the G-X-Y repeat region in the triple helical col lagen domain are strongly associated with EDS IV (Pepin 2000, Pepin 2014, Frank 2015), where this variant is located. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Gly252Cys variant is likely pathogenic. |
| Labcorp Genetics |
RCV000222891 | SCV001411661 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2019-07-31 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228249). 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 is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 252 of the COL3A1 protein (p.Gly252Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. |
| Gene |
RCV001589122 | SCV001815398 | pathogenic | not provided | 2019-09-16 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Located in the triple-helical region; Has not been previously published as pathogenic or benign to our knowledge; No data available from control populations to assess the frequency of this variant |