ClinVar Miner

Submissions for variant NM_000474.4(TWIST1):c.358C>T (p.Arg120Cys) (rs1233220987)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000808616 SCV000948730 pathogenic Craniosynostosis 1; Saethre-Chotzen syndrome 2019-03-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 120 of the TWIST1 protein (p.Arg120Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Saethre-Chotzen syndrome (PMID: 15923834, 18391498) and was also observed to be de novo in an individual affected with craniosynostosis (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.R120 amino acid residue in TWIST1. Other variant(s) that disrupt this residue have been observed in individuals with TWIST1-related conditions (PMID: 10649491), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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