ClinVar Miner

Submissions for variant NM_001163213.1(FGFR3):c.746C>G (p.Ser249Cys) (rs121913483)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000297175 SCV000329833 pathogenic not provided 2017-11-24 criteria provided, single submitter clinical testing The S249C missense variant in the FGFR3 gene has been reported in association with thanatophoric dysplasia I (TDI) and is one of five common, recurrent pathogenic variants responsible for this severe skeletal dysplasia (Rousseau et al., 1996; Tavormina et al., 1995; Del Piccolo et al. 2015). Functional studies indicate that S249C results in stable dimerization of the mutant protein and constitutive phosphorylation of the receptor (Tomlinson et al., 2007; Del Piccolo et al. 2015). It 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 conserved position within the linker region between Ig-like II and III where multiple disease-associated variants occur in the FGFR family of genes. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Another missense substitution to a cysteine at a nearby residue (R248C) also has been reported in association with TDI according to the Human Gene Mutation Database (Stenson et al., 2014). Finally, the S249C missense variant is not observed in large population cohorts (Lek et al., 2016). In summary, S249C is a common pathogenic variant and its presence is consistent with a diagnosis of thanatophoric dysplasia.
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000017744 SCV000584006 pathogenic Urinary bladder cancer 2017-07-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763119 SCV000893664 pathogenic Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Carcinoma of cervix; Crouzon syndrome with acanthosis nigricans; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Urinary bladder cancer; Hypochondroplasia; Epidermal nevus; Severe achondroplasia with developmental delay and acanthosis nigricans; Malignant tumor of testis; Carcinoma of colon 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000800158 SCV000939858 pathogenic Craniosynostosis 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 249 of the FGFR3 protein (p.Ser249Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs121913483, ExAC 0.002%). This variant has been observed in several individuals affected with thanatophoric dysplasia (PMID: 8589699, 11038465, 11879084). ClinVar contains an entry for this variant (Variation ID: 16339). Experimental studies have shown that this missense change results in stable FGFR3 dimerization and constitutive phosphorylation of the receptor at higher levels than wild type protein (PMID: 17384684, 19749790, 25606676). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000950 SCV001158049 pathogenic not specified 2018-12-22 criteria provided, single submitter clinical testing The FGFR3 c.746C>G; p.Ser249Cys variant (rs121913483) is one of the common FGFR3 missense variants that has been described in association with thanatophoric dysplasia type 1 (TD1; De Biasio 2000, Jung 2017, Rousseau 1996, Tavormina 1995). It is reported as pathogenic in ClinVar (Variation ID: 16339) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Functional studies of the variant protein demonstrate stable dimerization and constitutive activation in the absence of a ligand (Del Piccolo 2015, Tomlinson 2007). Based on available information, this variant is considered pathogenic. REFERENCES De Biasio P et al. Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation. Prenat Diagn. 2000 Oct;20(10):835-7. Del Piccolo N et al. Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization. Biophys J. 2015 Jan 20;108(2):272-8. Jung M et al. Genetically confirmed thanatophoric dysplasia with fibroblast growth factor receptor 3 mutation. Exp Mol Pathol. 2017 Apr;102(2):290-295. Rousseau F et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet. 1996 Apr;5(4):509-12. Tavormina P et al. Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. Hum Mol Genet. 1995 Nov;4(11):2175-7. Tomlinson D et al. Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Oncogene. 2007 Aug 30;26(40):5889-99.
OMIM RCV000017742 SCV000038020 pathogenic Thanatophoric dysplasia type 1 2005-05-01 no assertion criteria provided literature only
OMIM RCV000017743 SCV000038021 pathogenic Carcinoma of cervix 2005-05-01 no assertion criteria provided literature only
OMIM RCV000017744 SCV000038022 pathogenic Urinary bladder cancer 2005-05-01 no assertion criteria provided literature only
OMIM RCV000017745 SCV000038023 pathogenic Seborrheic keratosis 2005-05-01 no assertion criteria provided literature only
GeneReviews RCV000017742 SCV000086718 pathologic Thanatophoric dysplasia type 1 2013-09-12 no assertion criteria provided curation Converted during submission to Pathogenic.
Database of Curated Mutations (DoCM) RCV000431989 SCV000504978 likely pathogenic Bladder carcinoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435437 SCV000506421 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417690 SCV000506422 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424421 SCV000506423 likely pathogenic Carcinoma 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438171 SCV000506424 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420501 SCV000506425 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Baylor Genetics RCV000017742 SCV000854615 pathogenic Thanatophoric dysplasia type 1 2018-11-18 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.