ClinVar Miner

Submissions for variant NM_000141.4(FGFR2):c.758C>G (p.Pro253Arg) (rs77543610)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000014193 SCV000854607 pathogenic Acrocephalosyndactyly type I 2018-11-18 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000436870 SCV000505296 likely pathogenic Head and Neck Neoplasms 2014-12-26 no assertion criteria provided literature only
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000014193 SCV000328369 pathogenic Acrocephalosyndactyly type I 2016-09-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762803 SCV000893153 pathogenic Acrocephalosyndactyly type I; Cutis Gyrata syndrome of Beare and Stevenson; Jackson-Weiss syndrome; Levy-Hollister syndrome; Pfeiffer syndrome; Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis; Crouzon syndrome; Saethre-Chotzen syndrome; Scaphocephaly, maxillary retrusion, and mental retardation; Neoplasm of stomach; Bent bone dysplasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000489611 SCV000577419 pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The P253R variant in the FGFR2 gene has been reported many times in association with FGFR2-related disorders (Wilkie et al., 1995; Slaney et al., 1996; Ibarra-Arce et al., 2015). Functional studies show a gain of function resulting in increased ligand binding and receptor activation of the mutant receptor (Anderson et al., 1998). The P253R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P253R 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 and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P253R as a pathogenic variant.
GeneReviews RCV000014193 SCV000929992 pathogenic Acrocephalosyndactyly type I 2019-05-20 no assertion criteria provided literature only
Invitae RCV000532721 SCV000659619 pathogenic FGFR2 related craniosynostosis 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 253 of the FGFR2 protein (p.Pro253Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant is one of two missense changes in exon 7 of the FGFR2 gene that are known to cause the majority of Apert syndrome cases.  This particular variant is estimated to be the cause for approximately 20-40% of all Apert syndrome cases (PMID: 8651276, 7668257, 7719344, 25867380, 24656465, 9677057, 17251833).  ClinVar contains an entry for this variant (Variation ID: 13273). Experimental studies have shown that this missense change increases the ligand affinity of the FGFR2 protein leading to an increase in signaling activty (PMID: 9700203, 20489451, 15389579). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014193 SCV000034441 pathogenic Acrocephalosyndactyly type I 2006-10-15 no assertion criteria provided literature only

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