ClinVar Miner

Submissions for variant NM_000474.4(TWIST1):c.395_415del (p.Arg132_Leu138del) (rs1554441992)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000554759 SCV000657551 uncertain significance Craniosynostosis 1; Saethre-Chotzen syndrome 2017-07-19 criteria provided, single submitter clinical testing This variant, c.395_415del, results in the deletion of 7 amino acids of the TWIST1 protein (p.Arg132_Leu138del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TWIST1-related disease. This deletion 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). A significant number of TWIST1 missense mutations are reported within this deleted region in individuals and families with craniosynostosis and Saethre-Chotzen syndrome (PMID: 20184424, 15923834, 9792856, 24127277, 16251895, 19483581). These observations suggest that this deletion may affect protein function, but experimental studies and prediction algorithms are not available for this variant. Therefore, the functional significance of the deleted amino acids is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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