ClinVar Miner

Submissions for variant NM_000474.4(TWIST1):c.329G>C (p.Arg110Pro) (rs1085307555)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489759 SCV000576716 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing The R110P variant in the TWIST1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R110P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R110P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R110P as a variant of uncertain significance.
Invitae RCV000802635 SCV000942476 likely pathogenic Craniosynostosis 1; Saethre-Chotzen syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 110 of the TWIST1 protein (p.Arg110Pro). 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 not been reported in the literature in individuals with TWIST1-related disease. ClinVar contains an entry for this variant (Variation ID: 426307). 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. 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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