Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000826160 | SCV000967696 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2018-02-09 | criteria provided, single submitter | clinical testing | The p.Gly756Glu variant in COL3A1 (also described as p.Gly589Glu in the literatu re) has been reported in 1 individual with clinical features of Ehlers-Danlos sy ndrome type IV and segregated with disease in 3 affected relatives, including on e obligate carrier, from 1 family (Madhatheri 1994). This variant was absent fro m large population studies. Computational prediction tools and conservation anal ysis suggest that the p.Gly756Glu variant may impact the protein. Variants in CO L3A1 affecting conserved glycine (Gly) residues of the G-X-Y repeat region in th e triple helical collagen domain, where this variant is located, are strongly as sociated with EDS IV (Pepin 2000, Pepin 2014, Frank 2015). In summary, although additional studies are required to fully establish its clinical significance, th e p.Gly756Glu variant is likely pathogenic. ACMG/AMP Criteria applied (Richards 2015): PS4_Supporting, PM2, PP3, PM1. |
| Invitae | RCV000826160 | SCV001230593 | pathogenic | Ehlers-Danlos syndrome, type 4 | 2019-12-06 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 756 of the COL3A1 protein (p.Gly756Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant has been observed in individual(s) with Ehlers-Danlos syndrome (PMID: 7912131). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly589Glu. in the literature. ClinVar contains an entry for this variant (Variation ID: 667403). 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). For these reasons, this variant has been classified as Pathogenic. 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"). |