chr4-1801841-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000142.5(FGFR3):c.746C>G(p.Ser249Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
FGFR3
NM_000142.5 missense
NM_000142.5 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 7.48
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 4-1801841-C-G is Pathogenic according to our data. Variant chr4-1801841-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 16339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1801841-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FGFR3 | NM_000142.5 | c.746C>G | p.Ser249Cys | missense_variant | 7/18 | ENST00000440486.8 | NP_000133.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FGFR3 | ENST00000440486.8 | c.746C>G | p.Ser249Cys | missense_variant | 7/18 | 5 | NM_000142.5 | ENSP00000414914.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 39
GnomAD4 exome
Cov.:
39
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ExAC
AF:
AC:
1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:25Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 13, 2020 | 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. - |
| 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 | Clinical Genetics and Genomics, Karolinska University Hospital | Jun 07, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | 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). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 14, 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 | Revvity Omics, Revvity | Aug 31, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2021 | 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) - |
Thanatophoric dysplasia type 1 Pathogenic:5Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jul 22, 2023 | 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. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2005 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Nov 18, 2018 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Cervical cancer Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2005 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP5,PP4,PP3. - |
Malignant tumor of urinary bladder Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2005 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Bioinformatics dept., Datar Cancer Genetics Limited, India | Jul 24, 2017 | - - |
Malignant neoplastic disease Other:2
| -, criteria provided, single submitter | curation | Wagner Lab, Nationwide Children's Hospital | Feb 16, 2024 | FGFR3 S249C drug sensitivity studies show clinical and in vitro sensitivity to erdafitnib (civic.EID:7306). Functional and oncogenic studies indicate ligand-independent dimerization, autophosphorylation, substrate phosphorylation, MAPK activation, proliferation, tumor growth in nude mice, anchorage-independent growth, and morphological transformation, supporting ClinGen/CGC/VICC oncogenicity criteria OS2 (civic.EID:10386, civic.EID:8855). In cancerhotspots.org, all 114 FGFR3 samples with a mutation at position 249 had the same amino acid change from S to C supporting criteria OS3. FGFR3 S249C was absent in gnomAD (v2.1.1) supporting criteria OP4, and many in silico algorithms predict S249C to have damaging effects supporting criteria OP1. These criteria in total result in an oncogenicity score of 10 points, which categorizes FGFR3 S249C as an oncogenic variant. - |
| -, criteria provided, single submitter | curation | CIViC knowledgebase, Washington University School of Medicine | Feb 16, 2024 | FGFR3 S249C drug sensitivity studies show clinical and in vitro sensitivity to erdafitnib (civic.EID:7306). Functional and oncogenic studies indicate ligand-independent dimerization, autophosphorylation, substrate phosphorylation, MAPK activation, proliferation, tumor growth in nude mice, anchorage-independent growth, and morphological transformation, supporting ClinGen/CGC/VICC oncogenicity criteria OS2 (civic.EID:10386, civic.EID:8855). In cancerhotspots.org, all 114 FGFR3 samples with a mutation at position 249 had the same amino acid change from S to C supporting criteria OS3. FGFR3 S249C was absent in gnomAD (v2.1.1) supporting criteria OP4, and many in silico algorithms predict S249C to have damaging effects supporting criteria OP1. These criteria in total result in an oncogenicity score of 10 points, which categorizes FGFR3 S249C as an oncogenic variant. - |
Seborrheic keratosis Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2005 | - - |
Squamous cell lung carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing;in vivo | Faculté Pluridciplinaire Nador, Université Mohamed Premier | May 05, 2020 | - - |
Thanatophoric dysplasia, type 2;C1868678:Thanatophoric dysplasia type 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PP3_Moderate+PS4+PM6_VeryStrong - |
Achondroplasia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
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 | - - |
See cases Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University | Nov 29, 2021 | - - |
FGFR3-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 28, 2022 | 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. - |
Connective tissue disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 06, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;T;.;.;T;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
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;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;.;D;D
Sift4G
Benign
T;T;T;T;D;T;D
Polyphen
D;D;D;D;.;D;.
Vest4
MutPred
Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);.;
MVP
MPC
0.63
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