Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000533193 | SCV000630087 | pathogenic | Saethre-Chotzen syndrome | 2017-06-14 | criteria provided, single submitter | clinical testing | This variant, c.397_417dup, results in the insertion of 7 amino acids to the TWIST1 protein (p.Lys133_Pro139dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with craniosynostosis and was observed to arise de novo in one case (PMID: 8988167, 16838304). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This insertion is located within the conserved loop region of the basic helix-loop-helix (bHLH) domain of the TWIST1 protein. The bHLH domain is essential for protein dimerization and DNA-binding (PMID: 11992718). Four different 7 amino acid in-frame duplications in the loop region have been reported in affected individuals (PMID: 24127277, 16251895, 14513358), which suggests that insertions in this region are deleterious. For these reasons, this variant has been classified as Pathogenic. |