Submissions for variant NM_000142.5(FGFR3):c.742C>T (p.Arg248Cys) (rs121913482)

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine	RCV000017731	SCV000282235	pathogenic	Thanatophoric dysplasia type 1	2016-06-22	criteria provided, single submitter	clinical testing	PS2 De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. PS3 Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000017731	SCV000328407	pathogenic	Thanatophoric dysplasia type 1	2016-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000327823	SCV000329627	pathogenic	not provided	2019-12-05	criteria provided, single submitter	clinical testing	Reported many times in association with thanatophoric dysplasia type 1 (TD1) and is one of five common, recurrent pathogenic variants responsible for this severe skeletal dysplasia (Rousseau et al., 1996; Wilcox et al., 1998; Tavormina et al., 1995; Del Piccolo et al., 2015); Accounts for approximately 50% of thanatophoric dysplasia cases (Wilcox et al., 1998); Published functional studies indicate R248C alters FGFR3 dimer stabilization, activates FGFR3 by forming covalently bound dimers via disuldide bonds, and stimulates ERK phosphorylation (Del Piccolo et al., 2015; Foldynova-Trantirkova et al., 2012; Duperret et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24038754, 21639936, 16778799, 22106050, 20704477, 25671245, 8845844, 25606676, 20420824, 22045636, 23551494, 11241532, 24626198, 23786770, 19422094, 9215781, 17441958, 7773297, 18642369, 11754059, 27433940, 16841094, 19088846, 12108063, 17048442, 17375526, 20711586, 9182787, 29620724, 19789973, 30692697, 31299979, 31395954, 31218223, 31006186, 12833394, 9677066, 31994750, 32360156, 32668031, 32333414, 33258288)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000327823	SCV000334262	pathogenic	not provided	2018-08-13	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000414822	SCV000492884	pathogenic	Skeletal dysplasia; Short stature; Growth delay; Short ribs; Narrow chest; Small for gestational age; Bell-shaped thorax; Femoral bowing; Bowed humerus; Disproportionate short-limb short stature; Lethal short-limbed short stature; Lower limb undergrowth; Upper limb undergrowth	2015-05-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000999989	SCV000603712	pathogenic	none provided	2020-06-01	criteria provided, single submitter	clinical testing	The FGFR3 c.742C>T; p.Arg248Cys variant (rs121913482) is one of the most common FGFR3 variants identified in cases of autosomal dominant thanatophoric dysplasia (TD) (Tavormina 1995, Wilcox 1998). In one cohort, the p.Arg248Cys variant was identified in 45 out of 91 cases of TD (Wilcox 1998). Additionally, genotyping has demonstrated that this variant is absent in both parents of some affected individuals (Tavormina 1995, Takagi 2012), suggesting it may frequently arise de novo. While the majority of variant carriers are severely affected, p.Arg248Cys has also been identified in patients with milder forms of skeletal dysplasia, which is typically attributed to somatic mosaicism of the p.Arg248Cys variant (Hyland 2003, Takagi 2012). Recent functional studies have indicated the p.Arg248Cys variant promotes ligand-independent FGFR3 dimerization (Del Piccolo 2015), which is predicted to result in constitutive receptor activation, as is observed with other cysteine-substituted FGFR3 variants associated with TD type I (Adar 2002). Based on available information, this variant is considered to be pathogenic. References: Adar R et al. Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization. J Bone Miner Res. 2002 May;17(5):860-8. Del Piccolo N et al. Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization. Biophys J. 2015 Jan 20;108(2):272-8. Hyland VJ et al. Somatic and germline mosaicism for a R248C missense mutation in FGFR3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia. Am J Med Genet A. 2003 Jul 15;120A(2):157-68. Takagi M et al. Atypical achondroplasia due to somatic mosaicism for the common thanatophoric dysplasia mutation R248C. Am J Med Genet A. 2012 Jan;158A(1):247-50. Tavormina PL et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. 1995 Mar;9(3):321-8. Wilcox WR et al. Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. Am J Med Genet. 1998 Jul 7;78(3):274-81.
Fulgent Genetics,Fulgent Genetics	RCV000763118	SCV000893663	pathogenic	Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cancer 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
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001196297	SCV001366881	pathogenic	Cancer of cervix	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Invitae	RCV001217632	SCV001389479	pathogenic	Craniosynostosis syndrome	2019-06-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 248 of the FGFR3 protein (p.Arg248Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant is one of the most common causes of thanatophoric dysplasia and has been observed in several affected individuals (PMID: 10696568, 7773297, 11241532), including at least one case which was observed to be de novo (PMID: 7773297). ClinVar contains an entry for this variant (Variation ID: 16332). This variant has been reported to affect FGFR3 protein function (PMID: 1908846, 25606676). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital	RCV000327823	SCV001450204	pathogenic	not provided	2017-05-10	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526641	SCV001737072	pathogenic	Hamartoma		criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000327823	SCV001832516	pathogenic	not provided	2020-03-13	criteria provided, single submitter	clinical testing
OMIM	RCV000017731	SCV000038009	pathogenic	Thanatophoric dysplasia type 1	2008-09-01	no assertion criteria provided	literature only
OMIM	RCV000017732	SCV000038010	pathogenic	Multiple myeloma	2008-09-01	no assertion criteria provided	literature only
OMIM	RCV000017733	SCV000038011	pathogenic	Skeletal dysplasia with acanthosis nigricans	2008-09-01	no assertion criteria provided	literature only
OMIM	RCV000017734	SCV000038012	pathogenic	Epidermal nevus	2008-09-01	no assertion criteria provided	literature only
OMIM	RCV000017735	SCV000038013	pathogenic	Seborrheic keratosis	2008-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000017731	SCV000086717	pathologic	Thanatophoric dysplasia type 1	2013-09-12	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Database of Curated Mutations (DoCM)	RCV000420041	SCV000505529	likely pathogenic	Lung adenocarcinoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000017732	SCV000506416	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425802	SCV000506417	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432622	SCV000506418	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443913	SCV000506419	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425165	SCV000506420	likely pathogenic	Carcinoma	2016-05-13	no assertion criteria provided	literature only
Baylor Genetics	RCV000017731	SCV000854614	pathogenic	Thanatophoric dysplasia type 1	2018-11-18	no assertion criteria provided	clinical testing
Institute of Human Genetics, Klinikum rechts der Isar	RCV000017731	SCV001430109	pathogenic	Thanatophoric dysplasia type 1	2016-12-08	no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000327823	SCV001955168	pathogenic	not provided		no assertion criteria provided	clinical testing