Submissions for variant NM_000142.5(FGFR3):c.746C>G (p.Ser249Cys)

dbSNP: rs121913483

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000297175	SCV000329833	pathogenic	not provided	2021-01-05	criteria provided, single submitter	clinical testing	Published functional studies indicate that S249C results in stable dimerization of the mutant protein and constitutive phosphorylation of the receptor (Tomlinson et al., 2007). Furthermore, activation of FGFR3 was shown to be associated with an increase in FGFR3b isoform expression in S249C mutated tumors compared to normal tissue (Rosty et al., 2005).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; No data available from ethnically-matched control populations to assess the frequency of this variant; Reported in ClinVar as pathogenic but additional evidence is not available (ClinVar Variant ID# 16339; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22229528, 15772091, 19422094, 10471491, 22899908, 23175443, 11078763, 19381019, 25606676, 31754721, 25614871, 11038465, 8589699, 15869706, 17384684, 12461689, 11114733, 11904459, 21264819, 25928347, 27786351, 11879084, 28249712, 30692697, 19749790, 26619011, 25157968, 30952872, 8845844)
Bioinformatics dept., Datar Cancer Genetics Limited, India	RCV000017744	SCV000584006	pathogenic	Malignant tumor of urinary bladder	2017-07-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763119	SCV000893664	pathogenic	Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Malignant tumor of urinary bladder; Hypochondroplasia; Epidermal nevus; Severe achondroplasia-developmental delay-acanthosis nigricans syndrome; Malignant tumor of testis; Carcinoma of colon	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000297175	SCV000939858	pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 249 of the FGFR3 protein (p.Ser249Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with thanatophoric dysplasia (PMID: 8589699, 11038465, 11879084). ClinVar contains an entry for this variant (Variation ID: 16339). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt FGFR3 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 17384684, 19749790, 25606676). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000297175	SCV001158049	pathogenic	not provided	2020-04-13	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000017743	SCV001366474	pathogenic	Cervical cancer	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP5,PP4,PP3.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000297175	SCV001449919	pathogenic	not provided	2018-06-07	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000297175	SCV001832506	pathogenic	not provided	2020-02-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000297175	SCV002023071	pathogenic	not provided	2021-08-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276554	SCV002566637	pathogenic	Connective tissue disorder	2022-06-06	criteria provided, single submitter	clinical testing
Suma Genomics	RCV000017742	SCV002572512	pathogenic	Thanatophoric dysplasia type 1		criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000017742	SCV003841873	pathogenic	Thanatophoric dysplasia type 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016339). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 25614871). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV004532377	SCV004114922	pathogenic	FGFR3-related disorder	2022-11-28	criteria provided, single submitter	clinical testing	The FGFR3 c.746C>G variant is predicted to result in the amino acid substitution p.Ser249Cys. This variant has been reported to be causative for thanatophoric dysplasia in multiple patients (De Biasio et al. 2000. PubMedID: 11038465; Xue et al. 2014. PubMed ID: 25614871; Zhang et al. 2019. PubMed ID: 30692697). It has been reported as a de novo finding and functional studies support its pathogenicity (Peng et al. 2021. PubMed ID: 34567078; Del Piccolo et al. 2015. PubMed ID: 25606676). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989294	SCV004807444	pathogenic	Achondroplasia	2024-03-26	criteria provided, single submitter	clinical testing
Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics	RCV000017742	SCV005091226	pathogenic	Thanatophoric dysplasia type 1	2024-07-20	criteria provided, single submitter	research	This variant is de novo in origin in a patient with a disease and no family history (PS2_strong). The variant was reported as pathogenic in ClinVar (30 submissions) (PS4_strong) and it is absent from gnomAD population database (PM2_supporting). In addition multple lines of computational evidence support a deleterious effect of the variant on the gene or gene product (PP3_moderate).
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795921	SCV005417178	pathogenic	Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Moderate+PS4+PM6_VeryStrong
Neuberg Centre For Genomic Medicine, NCGM	RCV000017742	SCV005438798	pathogenic	Thanatophoric dysplasia type 1	2023-07-22	criteria provided, single submitter	clinical testing	The observed missense c.746C>G p.Ser249Cys variant in FGFR3 gene has been reported in multiple individuals affected with thanatophoric dysplasia Tavormina et al., 1995; De Biasio et al., 2000; Xue et al., 2014. Experimental studies have shown that this missense change affects FGFR3 function Tomlinson et al., 2007; di Martino et al., 2009; Del Piccolo et al., 2015. This variant is present with allele frequency of 0.00% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/ Pathogenic multiple submissions. Multiple lines of computational evidence Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Ser249Cys in FGFR3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 249 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000017742	SCV000038020	pathogenic	Thanatophoric dysplasia type 1	2005-05-01	no assertion criteria provided	literature only
OMIM	RCV000017743	SCV000038021	pathogenic	Cervical cancer	2005-05-01	no assertion criteria provided	literature only
OMIM	RCV000017744	SCV000038022	pathogenic	Malignant tumor of urinary bladder	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	not provided	Thanatophoric dysplasia type 1		no assertion provided	literature only
Baylor Genetics	RCV000017742	SCV000854615	pathogenic	Thanatophoric dysplasia type 1	2018-11-18	no assertion criteria provided	clinical testing
Faculté Pluridciplinaire Nador, Université Mohamed Premier	RCV000420501	SCV001250917	likely pathogenic	Squamous cell lung carcinoma	2020-05-05	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000297175	SCV001951116	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000297175	SCV001965568	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	RCV003155033	SCV003844085	pathogenic	See cases	2021-11-29	no assertion criteria provided	research