ClinVar Miner

Submissions for variant NM_000141.5(FGFR2):c.833G>T (p.Cys278Phe) (rs776587763)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255197 SCV000322318 pathogenic not provided 2016-03-01 criteria provided, single submitter clinical testing he C278F pathogenic variant in the FGFR2 gene has been previously reported as a de novo heterozygous variant in six individuals with typical features of Crouzon syndrome and was confirmed de novo in three of those individuals (Oldridge et al., 1995). The C278F variant has been shown to segregate with affected individuals within families with Crouzon syndrome (Oldridge et al., 1995; Sangong et al., 2014) and has also been reported de novo in a female with cloverleaf skull, microcephaly secondary to pansynostosis of the calvarial sutures, proptosis, and slightly broad thumbs and big toes (Steinberger et al., 1999). The C278F 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. The C278F 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. Functional studies suggest that the C278F variant results in a gain of function of the receptor resulting in negative autoregulation and advanced fetal cranial ossification (Britto et al., 2001). In vivo functional studies in chicken embryos also showed the variant is gain of function and produced midface hypoplasia and hypertelorism during the early stages of facial morphogenesis (Li et al., 2013). Missense variants at the same (C278Y) and nearby residues (F276V, Y281C, S282C) have been reported in the Human Gene Mutation Database in association with Crouzon syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000415498 SCV000328372 pathogenic Pfeiffer syndrome 2016-09-17 criteria provided, single submitter clinical testing
Invitae RCV000557313 SCV000659621 pathogenic FGFR2 related craniosynostosis 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 278 of the FGFR2 protein (p.Cys278Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs776587763, ExAC 0.001%). This variant is one of the most common causes of Crouzon syndrome and has been reported in many affected individuals (PMID: 7655462, 24127277, 25361936). It has also been observed in individuals affected with Pfeiffer syndrome or multisuture craniosynostosis (PMID: 10874645, 23348274, 24127277). In many of these individuals, this variant has been shown to arise de novo (PMID: 7655462, 23348274). For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000844883 SCV000926259 pathogenic Crouzon syndrome 2019-06-24 criteria provided, single submitter clinical testing A heterozygous missense variant in exon 7 of the FGFR2 gene that results in the amino acid substitution of Phenylalanine for Cystine at codon 278 was detected. The observed variation lies in the immunoglobuline set domain of the FGFR2 protein and has previously been reported in patients affected with Crouzon syndrome and functional studies show the pathogenic affect of the observed variant (Li et al. Hum Mol Genet 2013). The variant has not been reported in the 1000 genomes database and has allele frequency of 0.001% in ExAC database. In silico predictions show possibly damaging by PolyPhen-2 and damaging by SIFT, LRT and MutationTaster. In summary, the said variant meets our criteria to be classified as uncertain significance based on the mode of inheritance, in silico prediction and allele frequency in population databases.

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