Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000653733 | SCV000775623 | pathogenic | TWIST1-related craniosynostosis; Saethre-Chotzen syndrome | 2022-02-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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). Two different 7 amino acid in-frame duplications in the loop region have been reported in individuals affected with Saethre-Chotzen syndrome (PMID: 16251895, 14513358) and a different variant (c.397_417dup21) giving rise to the same protein effect observed here (p.Lys133_Pro139dup) has also been reported in an individual affected with Saethre-Chotzen syndrome (PMID: 8988167, 16251895), which suggests that insertions in this region are deleterious. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 543075). This variant is also known as "type 1 duplication", "416ins21" and "416_417dup21" (PMID: 8988167, 8988166, 14513358). This variant has been observed in individual(s) with Saethre-Chotzen syndrome (PMID: 8988166, 8988167, 11992718, 14513358, 16251895, 19755431, 20643727). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.396_416dup, results in the insertion of 7 amino acid(s) of the TWIST1 protein (p.Lys133_Pro139dup), but otherwise preserves the integrity of the reading frame. |
Ce |
RCV001092558 | SCV001249114 | pathogenic | not provided | 2019-07-01 | criteria provided, single submitter | clinical testing |