ClinVar Miner

Submissions for variant NM_000474.4(TWIST1):c.396_416dup (p.Lys133_Pro139dup) (rs1554441991)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000653733 SCV000775623 pathogenic Craniosynostosis 1; Saethre-Chotzen syndrome 2019-12-03 criteria provided, single submitter clinical testing This variant, c.396_416dup21, 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 to segregate with Saethre-Chotzen syndrome in several families (PMID: 8988167, 8988166). This variant has been reported in individuals affected with Saethre-Chotzen syndrome (PMID: 20643727, 19755431, 8988167, 14513358). This variant is also known as "type 1 duplication", "416ins21" and "416_417dup21" (PMID: 8988167, 8988166, 14513358). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. 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). 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. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001092558 SCV001249114 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing

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