ClinVar Miner

Submissions for variant NM_000141.5(FGFR2):c.758C>T (p.Pro253Leu) (rs77543610)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001029732 SCV001192518 uncertain significance Acrocephalosyndactyly type I 2019-11-19 criteria provided, single submitter research ACMG codes: PS4M, PM2, PP3
Invitae RCV001228029 SCV001400411 likely pathogenic FGFR2 related craniosynostosis 2019-08-07 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 253 of the FGFR2 protein (p.Pro253Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with craniosynostosis syndromes (PMID: 15863034, 24127277, 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Pro253 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7668257, 7719344, 8651276, 9700203). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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