ClinVar Miner

Submissions for variant NM_000474.4(TWIST1):c.446T>G (p.Leu149Arg)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001035938 SCV001199278 uncertain significance Craniosynostosis 1; Saethre-Chotzen syndrome 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 149 of the TWIST1 protein (p.Leu149Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. 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 conditions. 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.Leu149 amino acid residue in TWIST1. Other variant(s) that disrupt this residue have been observed in individuals with TWIST1-related conditions (PMID: 22982246, 9585583), which suggests that this may be a clinically significant amino acid residue. 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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