ClinVar Miner

Submissions for variant NM_000141.4(FGFR2):c.1025G>A (p.Cys342Tyr) (rs121918487)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000014173 SCV000510536 likely pathogenic Crouzon syndrome 2016-05-13 no assertion criteria provided literature only
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000014173 SCV000328393 pathogenic Crouzon syndrome 2016-09-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762801 SCV000893151 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
Invitae RCV000547490 SCV000659603 pathogenic FGFR2 related craniosynostosis 2018-07-10 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 342 of the FGFR2 protein (p.Cys342Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (rs121918487, ExAC no frequency). This variant is one of the most commonly observed variants in individuals affected with syndromic craniosynostosis, including Crouzon or Pfeiffer syndromes (PMID: 7987400, 24127277, 25271085). It has also been shown to segregate with Crouzon syndrome in a family (PMID: 8650126). ClinVar contains an entry for this variant (Variation ID: 13263). Experimental studies have shown that this missense change results in constitutive protein activity in cell culture, and a mouse model with this knock-in variant recapitulates many of the disease phenotypes (PMID: 22558232, 8755573, 20133659, 15316116). Several different missense substitutions at this codon (p.Cys342Arg, p.Cys342Ser, p.Cys342Trp) have been determined to be pathogenic (PMID: 24127277, 25271085). This suggests that the cysteine residue is critical for FGFR2 protein function, and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014173 SCV000034421 pathogenic Crouzon syndrome 1995-07-01 no assertion criteria provided literature only
OMIM RCV000014174 SCV000034422 pathogenic Pfeiffer syndrome 1995-07-01 no assertion criteria provided literature only

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