ClinVar Miner

Submissions for variant NM_000141.5(FGFR2):c.1052C>G (p.Ser351Cys) (rs121918502)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256107 SCV000322317 pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing The S351C missense variant in the FGFR2 gene has been reported previously in association with Pfeiffer syndrome and observed de novo (Gripp et al., 1998; Sweeney et al., 2002; Gonzales et al., 2005; Stevens et al., 2006; Chokdeemboon et al., 2013). The S351C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. S351C 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 by class where amino acids with similar properties to Serine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (S347C, S354C, S354F, S354Y) have been reported in the Human Gene Mutation Database in association with FGFR2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, S351C is considered a pathogenic variant.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000415503 SCV000328398 pathogenic Pfeiffer syndrome 2016-09-17 criteria provided, single submitter clinical testing
Invitae RCV000528973 SCV000659607 pathogenic FGFR2 related craniosynostosis 2019-03-12 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 351 of the FGFR2 protein (p.Ser351Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (rs121918502, ExAC no frequency). This variant has been reported as a frequent cause of craniosynostosis and has been observed in individuals affected with severe forms of Crouzon or Pfeiffer syndromes (PMID: 10406670, 16418739, 8946174, 23348274, 24656465). ClinVar contains an entry for this variant (Variation ID: 13286). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). However, substitutions that create or abolish cysteine residues in FGFR2 are commonly associated with craniosynostosis (PMID: 16418739, 18391498, 10406670). For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000415503 SCV000803777 pathogenic Pfeiffer syndrome 2015-07-30 criteria provided, single submitter clinical testing
OMIM RCV000014208 SCV000034456 pathogenic Pfeiffer syndrome, type III 2005-08-01 no assertion criteria provided literature only
OMIM RCV000014209 SCV000034457 pathogenic Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis 2005-08-01 no assertion criteria provided literature only

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