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

dbSNP: rs121913482

Total submissions: 52

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Shanghai First Maternity and Infant Hospital, Tongji University	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)
Eurofins Ntd Llc (ga)	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	RCV000327823	SCV000603712	pathogenic	not provided	2021-07-16	criteria provided, single submitter	clinical testing	The FGFR3 c.742C>T; p.Arg248Cys variant (rs121913482) is classified as pathogenic by several sources in the ClinVar database (Variation ID: 16332) and is described as 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). Functional studies indicate 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.
Baylor Genetics	RCV000017731	SCV000854614	pathogenic	Thanatophoric dysplasia type 1	2022-03-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763118	SCV000893663	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
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196297	SCV001366881	pathogenic	Cervical cancer	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000327823	SCV001389479	pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 248 of the FGFR3 protein (p.Arg248Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thanatophoric dysplasia (PMID: 7773297, 10696568, 11241532). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16332). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 1908846, 25606676). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000017731	SCV001430109	pathogenic	Thanatophoric dysplasia type 1	2016-12-08	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, 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
CeGaT Center for Human Genetics Tuebingen	RCV000327823	SCV001962549	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	FGFR3: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
Revvity Omics, Revvity	RCV000327823	SCV002023065	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001804739	SCV002053885	pathogenic	Achondroplasia		criteria provided, single submitter	clinical testing
DASA	RCV001849270	SCV002107095	pathogenic	FGFR3-related chondrodysplasia	2022-03-05	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 1908846; 25606676) - PS3_moderate.The c.742C>T;p.(Arg248Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 16332; PMID: 10696568; PMID: 7773297; PMID: 11241532) - PS4. This variant is not present in population databases (rs121913482- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 7773297) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Daryl Scott Lab, Baylor College of Medicine	RCV002243648	SCV002515325	pathogenic	FGFR3-related disorder	2022-02-01	criteria provided, single submitter	clinical testing
Mendelics	RCV001804739	SCV002516366	pathogenic	Achondroplasia	2022-05-04	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276552	SCV002566636	pathogenic	Connective tissue disorder	2022-07-05	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV000017731	SCV002567938	pathogenic	Thanatophoric dysplasia type 1	2022-08-22	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000017731	SCV002576369	pathogenic	Thanatophoric dysplasia type 1		criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000017731	SCV003920966	pathogenic	Thanatophoric dysplasia type 1	2022-07-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000327823	SCV004025948	pathogenic	not provided	2022-01-10	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003388567	SCV004100377	pathogenic	Thanatophoric dysplasia, type 2		criteria provided, single submitter	clinical testing	The R248C missense variant in the FGFR3 gene has been reported with thanatophoric dysplasia I (TDI) and is one of five common, recurrent pathogenic variants responsible for this severe skeletal dysplasia (Tavormina et al., 1995; Del Piccolo et al., 2015). 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). The variant has been submitted to ClinVar as Pathogenic. The p.R248C variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R248C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 248 of FGFR3 is conserved in all mammalian species. The nucleotide c.742 in FGFR3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000017731	SCV004123085	pathogenic	Thanatophoric dysplasia type 1	2023-07-01	criteria provided, single submitter	research
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000017734	SCV004176920	pathogenic	Epidermal nevus	2023-09-22	criteria provided, single submitter	clinical testing	The FGFR3 c.742C>T (p.Arg248Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in many individuals affected with epidermal nevi (Hafner C et al., PMID: 16841094; Bygum A et al., PMID: 21639936; Hafner C et al., PMID: 22499344; Collin B et al., PMID: 17441958; Hafner C et al., PMID: 17673550). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by many submitters in both a germline and somatic state (ClinVar Variation ID: 16332), and it has been reported in multiple cases in the cancer database COSMIC (COSMIC ID: COSV53390662). The FGFR3 c.742C>T (p.Arg248Cys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the ligand binding region of the extracellular domain, amino acids 23‚Äì375, of FGFR3, which is defined as a critical functional domain (Logié A et al., PMID: 15772091). Functional studies show that this variant leads to ligand-independent receptor activation, downstream activation of the mitogen-activated protein kinase pathway, increased cellular proliferation, and impaired apoptosis in multiple cell lines (Naski MC et al., PMID: 8640234; Hafner C et al., PMID: 20420824). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on FGFR3 function. Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the FGFR3 c.742C>T (p.Arg248Cys) variant is classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000017731	SCV004239071	pathogenic	Thanatophoric dysplasia type 1	2023-09-21	criteria provided, single submitter	clinical testing	c.742C>T in FGFR3 is a variant known to account for the majority (66.5%) of cases with thanatophoric dysplasia type I, with functional studies showing that it leads to ligand-independent FGFR3 dimerization. This variant has been reported in ClinVar (Variation ID 16332), but is absent from a large population dataset. We consider c.742C>T; p.Arg248Cys in FGFR3 to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804739	SCV004803862	pathogenic	Achondroplasia	2024-01-19	criteria provided, single submitter	clinical testing	Variant summary: FGFR3 c.742C>T (p.Arg248Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 236978 control chromosomes (gnomAD). c.742C>T has been reported in the literature in multiple individuals affected with Thanatophoric Dysplasia or Achondroplasia (examples: Gomes_2018 and Liu_2019). At-least one of these cases was reported as a de novo occurrence (Liu_2019). The following publications have been ascertained in the context of this evaluation (PMID: 29593476, 31299979). These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 16332). Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001804739	SCV004804902	pathogenic	Achondroplasia	2024-03-17	criteria provided, single submitter	research
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000327823	SCV005197924	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000017731	SCV005375478	pathogenic	Thanatophoric dysplasia type 1	2024-10-23	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000017731	SCV005399782	pathogenic	Thanatophoric dysplasia type 1	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with autosomal dominant skeletal dysplasias (OMIM). Additionally, autosomal recessive and dominant CATSHL syndrome (MIM#610474), is suspected to be due to variants with a loss of function, and dominant negative mechanism, respectively (PMID: 25614871, 24864036). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals with Muenke syndrome have been shown to inherit pathogenic variants from an asymptomatic parent (PMID: 26740388, 18000976). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a wide range of clinical symptoms with variable expressivity in LADD and Muenke syndrome patients, even within the same family (PMID: 26740388, 16501574). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified many times as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795425	SCV005417711	pathogenic	Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PS2+PS3_Moderate
Institute of Human Genetics, University Hospital Muenster	RCV003155030	SCV005419281	pathogenic	See cases	2024-10-10	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PS2,PS4,PM1,PM2
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798733	SCV005420723	pathogenic	Muenke syndrome	2024-10-04	criteria provided, single submitter	research	PS3,PS2,PM2,PP3
Neuberg Centre For Genomic Medicine, NCGM	RCV000017731	SCV005438689	pathogenic	Thanatophoric dysplasia type 1	2023-06-22	criteria provided, single submitter	clinical testing	The missense variant c.742C>Tp.Arg248Cys in FGFR3 gene has been observed in heterozygous state in multiple individuals with thanatophoric dysplasia Xue et. al., 2014; Hylandet. al., 2003; Chen et. al., 2001. Experimental studies have shown that this missense change affects FGFR3 function Del Piccolo et. al., 2015. The observed variant is absent in gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic multiple submitters. 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 change p.Arg248Cys in FGFR3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 248 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.
Fulgent Genetics, Fulgent Genetics	RCV005025063	SCV005662095	pathogenic	Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans 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; Colorectal cancer; Germ cell tumor of testis; Lacrimoauriculodentodigital syndrome 2	2024-05-17	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	not provided	Thanatophoric dysplasia type 1		no assertion provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000327823	SCV001955168	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000327823	SCV001974802	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000017731	SCV002072477	pathogenic	Thanatophoric dysplasia type 1	2022-01-30	no assertion criteria provided	clinical testing	The heterozygous mis-sense insertion variant c.742C>T (p.R248C) has been previously reported by Tavormina P L et al in 1995 and it has not been observed in gnomAD and 1000g. In-silico bioinformatic software predict this variant by mutation taster as Disease causing and SIFT & PROVEAN as Damaging. The phenotype observed was large head, short neck with increased nuchal thickness, protuberant abdomen and narrow thorax. Thanatophoric Dysplasia type I is an autosomal dominant disorder. Based on the phenotypic observation, we classify this variant as pathogenic.
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	RCV003155030	SCV003844074	pathogenic	See cases	2021-06-30	no assertion criteria provided	research
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000017731	SCV003927941	pathogenic	Thanatophoric dysplasia type 1	2023-04-01	no assertion criteria provided	clinical testing
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332082	SCV004040569	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV002243648	SCV004105863	pathogenic	FGFR3-related disorder	2024-03-29	no assertion criteria provided	clinical testing	The FGFR3 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Cys. This variant has repeatedly been reported to be causative for autosomal dominant thanatophoric dysplasia (Tavormina et al. 1995. PubMed ID: 7773297; Camera et al. 2001. PubMed ID: 11754059; Castori et al. 2013. PubMed ID: 24038754; Table S3b, Wojcik et al. 2019. PubMed ID: 31395954; Table S1, Maddirevula et al. 2018. PubMed ID: 29620724). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.