ClinVar Miner

Submissions for variant NM_000141.5(FGFR2):c.1024T>A (p.Cys342Ser) (rs121918488)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000415484 SCV000328391 pathogenic Pfeiffer syndrome 2016-09-17 criteria provided, single submitter clinical testing
GeneDx RCV000490034 SCV000577119 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing The C342S variant in the FGFR2 gene has been reported previously in association with FGFR2-related disorders (Reardon et al., 1994; Reardon et al., 2000; Begheri-Fam et al., 2015). The C342S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C342S 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. Additional missense variants in the same residue (C342R, C342G, C342Y, C342F, C342W) have also been reported in the Human Gene Mutation Database in association with FGFR2-related disorders (Stenson et al., 2014), supporting the functional importance of this residue of the protein. We interpret C342S as a pathogenic variant.
Invitae RCV000655416 SCV000777346 pathogenic FGFR2 related craniosynostosis 2018-11-04 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 342 of the FGFR2 protein (p.Cys342Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with syndromic craniosynostosis, including Pfeiffer and  Crouzen syndromes (PMID: 10541159, 25271085, 7987400). ClinVar contains an entry for this variant (Variation ID: 13267). Multiple different missense substitutions at this codon (p.Cys342Arg, p.Cys342Tyr, p.Cys342Trp) have been determined to be pathogenic (PMID: 24127277). This suggests that the cysteine residue is critical for FGFR2 protein function and that other missense substitutions at this position may also be pathogenic. A different variant (c.1025G>C) giving rise to the same protein effect observed here (p.Cys342Ser) has been reported in many individuals affected with syndromic craniosynostosis (PMID: 8644708, 12884434, 9586546, 24127277, 12884424,26362256, 25271085), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014181 SCV000034429 pathogenic Crouzon syndrome 2000-01-01 no assertion criteria provided literature only
OMIM RCV000014182 SCV000034430 pathogenic Jackson-Weiss syndrome 2000-01-01 no assertion criteria provided literature only
OMIM RCV000014183 SCV000034431 pathogenic Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis 2000-01-01 no assertion criteria provided literature only

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