Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000653736 | SCV000775626 | likely pathogenic | TWIST1-related craniosynostosis; Saethre-Chotzen syndrome | 2017-11-16 | criteria provided, single submitter | clinical testing | 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. Different missense substitutions at this codon (p.Arg116Trp, p.Arg116Leu) have been reported in individuals affected with  Saethre-Chotzen syndrome (PMID: 9585583, 17693524) suggesting that this amino acid is critical for protein function. 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. This variant has been reported in an individual affected with Saethre-Chotzen syndrome (PMID: 15923834) and in an individual in the Leiden Open-source Variation Database (PMID: 21520333). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 116 of the TWIST1 protein (p.Arg116Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. |