4-1801837-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000142.5(FGFR3):c.742C>T(p.Arg248Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
FGFR3
NM_000142.5 missense, splice_region
NM_000142.5 missense, splice_region
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 2.73
Genes affected
FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000142.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 4-1801837-C-T is Pathogenic according to our data. Variant chr4-1801837-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1801837-C-T is described in Lovd as [Pathogenic]. Variant chr4-1801837-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| FGFR3 | NM_000142.5 | c.742C>T | p.Arg248Cys | missense_variant, splice_region_variant | 7/18 | ENST00000440486.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FGFR3 | ENST00000440486.8 | c.742C>T | p.Arg248Cys | missense_variant, splice_region_variant | 7/18 | 5 | NM_000142.5 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 38
GnomAD4 exome
Cov.:
38
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:49Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Thanatophoric dysplasia type 1 Pathogenic:12Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Oct 20, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jul 18, 2022 | - - |
| Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 08, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jan 30, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Aug 22, 2022 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2008 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Sep 21, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Shanghai First Maternity and Infant Hospital, Tongji University | Jun 22, 2016 | 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 - |
not provided Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Jan 10, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 11, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 05, 2019 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 13, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 16, 2021 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | May 10, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 13, 2018 | - - |
Achondroplasia Pathogenic:4
| Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2024 | 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. - |
Multiple myeloma Pathogenic:2
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2008 | - - |
Epidermal nevus Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Sep 22, 2023 | 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. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2008 | - - |
FGFR3-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Feb 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 06, 2023 | 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 (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
FGFR3-related chondrodysplasia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | 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. - |
Seborrheic keratosis Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2008 | - - |
Carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Squamous cell lung carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Cervical cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. - |
Malignant tumor of urinary bladder Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory of Urology, Hospital Clinic de Barcelona | - | - - |
Skeletal dysplasia with acanthosis nigricans Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2008 | - - |
Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0153594:Malignant tumor of testis;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0410529:Hypochondroplasia;C0699790:Carcinoma of colon;C1300257:Thanatophoric dysplasia, type 2;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hamartoma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Thanatophoric dysplasia, type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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. - |
See cases Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University | Jun 30, 2021 | - - |
Lung adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Small for gestational age;C0345371:Lower limb undergrowth;C0349588:Short stature;C0410528:Skeletal dysplasia;C0426790:Narrow chest;C0426817:Short ribs;C0456070:Growth delay;C1837406:Upper limb undergrowth;C1849937:Disproportionate short-limb short stature;C1859460:Bowed humerus;C1859461:Femoral bowing;C1865186:Bell-shaped thorax;C2674171:Lethal short-limbed short stature Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 08, 2015 | - - |
Transitional cell carcinoma of the bladder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Connective tissue disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 05, 2022 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;T;.;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;H;H;.;H;.
MutationTaster
Benign
A;A;A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;.;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;D;D;D;.;D;.
Vest4
MutPred
Loss of disorder (P = 0.028);Loss of disorder (P = 0.028);Loss of disorder (P = 0.028);Loss of disorder (P = 0.028);Loss of disorder (P = 0.028);Loss of disorder (P = 0.028);.;
MVP
MPC
1.1
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at