ClinVar Miner

Submissions for variant NM_000474.4(TWIST1):c.443C>T (p.Thr148Ile)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001212895 SCV001384497 likely pathogenic Craniosynostosis 1; Saethre-Chotzen syndrome 2019-07-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 148 of the TWIST1 protein (p.Thr148Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of Saethre-Chotzen syndrome (PMID: 16251895, Invitae). 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 disrupts the p.Thr148 amino acid residue in TWIST1. Other variant(s) that disrupt this residue have been observed in individuals with TWIST1-related conditions (PMID: 9585583, 10649491, 16251895), which suggests that this may be a clinically significant amino acid residue. 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.

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