ClinVar Miner

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

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Total submissions: 27
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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

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