Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000533423 | SCV000631621 | likely pathogenic | Ehlers-Danlos syndrome, type 4 | 2017-05-27 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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, this variant is a rare missense change affecting a residue that is known to be critical for normal protein structure, stability and function. This type of missense change is also highly enriched in affected individuals and expected to be pathogenic. However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic. This variant has been reported in the literature in an individual affected with vascular Ehlers-Danlos syndrome (PMID: 22492385). ClinVar contains an entry for this variant (Variation ID: 199720). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 414 of the COL3A1 protein (p.Gly414Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. |