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

Total submissions: 17

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