ClinVar Miner

Submissions for variant NM_000474.4(TWIST1):c.395G>C (p.Arg132Pro) (rs1554441995)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526309 SCV000657552 pathogenic Craniosynostosis 1; Saethre-Chotzen syndrome 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 132 of the TWIST1 protein (p.Arg132Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Saethre-Chotzen syndrome (PMID: 9585583, Invitae). It has also been observed to segregate with disease in related individuals. 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.Arg132 amino acid residue in TWIST1. Other variant(s) that disrupt this residue have been observed in individuals with TWIST1-related conditions (PMID: 25271085, 19373776), 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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