ClinVar Miner

Submissions for variant NM_000141.4(FGFR2):c.799T>C (p.Ser267Pro) (rs121918505)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000408850 SCV000484911 pathogenic Crouzon syndrome no assertion criteria provided clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000014213 SCV000328370 pathogenic Pfeiffer syndrome 2016-09-17 criteria provided, single submitter clinical testing
GeneDx RCV000435703 SCV000516004 pathogenic not provided 2018-04-30 criteria provided, single submitter clinical testing The S267P variant in the FGFR2 gene has been reported previously, including de novo occurrences, in association with FGFR2-related craniosynostosis syndromes including Crouzon and Pfeiffer syndromes (Kan et al., 2002; Oldridge et al., 1995; Chokdeemboon et al., 2013). The S267P variant is not observed in large population cohorts (Lek et al., 2016). The S267P 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret S267P as a pathogenic variant.
Invitae RCV000690962 SCV000818693 pathogenic FGFR2 related craniosynostosis 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 267 of the FGFR2 protein (p.Ser267Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with Crouzon syndrome (PMID: 7655462, 11781872, 25759927) and Pfeiffer syndrome (PMID: 23348274, 10394936). In addition, this variant has also been reported to be sporadic in several individuals with Crouzon syndrome (PMID: 16418739, 24127277) or Pfeiffer syndrome (PMID: 10394936). This variant is also known as 811T>C.  ClinVar contains an entry for this variant (Variation ID: 13290). Experimental studies have shown that this missense change may result in inability to form a stable FGF2 ligand and receptor complex (PMID: 9700203). A different missense substitution at this codon (p.Ser267Phe) has been reported in an individual affected with Crouzon syndrome (PMID: 16418739). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014213 SCV000034461 pathogenic Pfeiffer syndrome 2001-05-01 no assertion criteria provided literature only
OMIM RCV000014214 SCV000034462 pathogenic Neoplasm of stomach 2001-05-01 no assertion criteria provided literature only

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