ClinVar Miner

Submissions for variant NM_000141.4(FGFR2):c.1124A>G (p.Tyr375Cys) (rs121913478)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224124 SCV000280700 pathogenic not provided 2014-08-28 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000441051 SCV000504807 likely pathogenic Endometrial neoplasm 2015-07-14 no assertion criteria provided literature only
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000014198 SCV000328400 pathogenic Cutis Gyrata syndrome of Beare and Stevenson 2016-09-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762799 SCV000893149 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 RCV000224124 SCV000322316 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing The Y375C pathogenic variant in the FGFR2 gene has been reported previously in multiple individuals with FGFR2-related craniosynostosis syndromes (Przylepa et al., 1996; Sureka et al., 2010; Wenger et al., 2015). The XY375C 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 Y375C variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (S372C) has been reported in the Human Gene Mutation Database in association with Beare-Stevenson cutis gyrata syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae RCV000549100 SCV000659609 pathogenic FGFR2 related craniosynostosis 2017-07-06 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 375 of the FGFR2 protein (p.Tyr375Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Beare-Stevenson cutis gyrata syndrome (PMID: 8696350, 27079505, 25706251, 12900900, 20856019, 21397175, 16531735, 12145519). In at least 2 of these cases, the was shown to be de novo (PMID: 8696350, 25937001). ClinVar contains an entry for this variant (Variation ID: 13277). 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: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014198 SCV000034446 pathogenic Cutis Gyrata syndrome of Beare and Stevenson 2007-11-01 no assertion criteria provided literature only
OMIM RCV000014199 SCV000034447 pathogenic Endometrial carcinoma 2007-11-01 no assertion criteria provided literature only

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