This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP5,PP4,PP3.
ClinVar Genomic variation as it relates to human health
NM_000142.5(FGFR3):c.746C>G (p.Ser249Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(30)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
30
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(2)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Oncogenic
2
criteria provided, multiple submitters, no conflicts
Variant Details
- Identifiers
-
NM_000142.5(FGFR3):c.746C>G (p.Ser249Cys)
Variation ID: 16339 Accession: VCV000016339.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4p16.3 4: 1801841 (GRCh38) [ NCBI UCSC ] 4: 1803568 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Apr 6, 2024 Mar 26, 2024 Somatic - Oncogenicity Feb 20, 2024 Feb 20, 2024 Feb 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000142.5:c.746C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000133.1:p.Ser249Cys missense NM_001163213.2:c.746C>G NP_001156685.1:p.Ser249Cys missense NM_001354809.2:c.746C>G NP_001341738.1:p.Ser249Cys missense NM_001354810.2:c.746C>G NP_001341739.1:p.Ser249Cys missense NM_022965.4:c.746C>G NP_075254.1:p.Ser249Cys missense NR_148971.2:n.1021C>G non-coding transcript variant NC_000004.12:g.1801841C>G NC_000004.11:g.1803568C>G NG_012632.1:g.13530C>G LRG_1021:g.13530C>G LRG_1021t1:c.746C>G LRG_1021p1:p.Ser249Cys P22607:p.Ser249Cys - Protein change
- S249C
- Other names
- -
- Canonical SPDI
- NC_000004.12:1801840:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
variation affecting protein function; Variation Ontology [ VariO:0003]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| FGFR3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
984 | 1134 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2023 | RCV000017742.43 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jan 1, 2016 | RCV000017743.16 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jul 24, 2017 | RCV000017744.14 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 1, 2005 | RCV000017745.14 | |
| Likely pathogenic (2) |
no assertion criteria provided
|
May 5, 2020 | RCV000420501.12 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000417690.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000424421.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000431989.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000438171.10 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Dec 11, 2023 | RCV000297175.29 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000435437.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763119.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 6, 2022 | RCV002276554.11 | |
|
See cases
|
Pathogenic (1) |
no assertion criteria provided
|
Nov 29, 2021 | RCV003155033.9 |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 26, 2024 | RCV003989294.2 | |
|
FGFR3-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Nov 28, 2022 | RCV004532377.2 |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Achondroplasia
Malignant tumor of urinary bladder Colorectal cancer Hypochondroplasia LADD syndrome 1 Epidermal nevus Thanatophoric dysplasia type 1 Thanatophoric dysplasia, type 2 Germ cell tumor of testis Muenke syndrome Cervical cancer Camptodactyly-tall stature-scoliosis-hearing loss syndrome Crouzon syndrome-acanthosis nigricans syndrome Severe achondroplasia-developmental delay-acanthosis nigricans syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893664.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jun 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
somatic
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449919.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cervical cancer
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366474.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP5,PP4,PP3.
|
|
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Pathogenic
(Apr 13, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158049.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021 |
Comment:
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 … (more)
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. (less)
|
|
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Pathogenic
(Nov 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
FGFR3-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004114922.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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. (less)
|
|
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Pathogenic
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000939858.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jul 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Malignant tumor of urinary bladder
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Bioinformatics dept., Datar Cancer Genetics Limited, India
Accession: SCV000584006.1
First in ClinVar: Jul 25, 2016 Last updated: Jul 25, 2016 |
Age: 80 years
Sex: male
Ethnicity/Population group: South asian
Geographic origin: India
|
|
|
Pathogenic
(Feb 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001832506.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Comment:
Patient analyzed with Comprehensive Skeletal Dysplasias and Disorders Panel
|
|
|
|
Pathogenic
(Jan 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329833.6
First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019 |
Comment:
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, … (more)
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) (less)
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Pathogenic
(Jun 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Connective tissue disorder
Affected status: unknown
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002566637.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Thanatophoric dysplasia type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Suma Genomics
Accession: SCV002572512.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Thanatophoric dysplasia type 1
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841873.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Hyperkeratosis (present) , Pruritus (present) , Intellectual disability, mild (present) , Attention deficit hyperactivity disorder (present) , Short stature (present) , Macrocephaly (present) , Seizure … (more)
Hyperkeratosis (present) , Pruritus (present) , Intellectual disability, mild (present) , Attention deficit hyperactivity disorder (present) , Short stature (present) , Macrocephaly (present) , Seizure (present) (less)
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Pathogenic
(Aug 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023071.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Achondroplasia
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807444.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(May 01, 2005)
|
no assertion criteria provided
Method: literature only
|
BLADDER CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000038022.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Tavormina et al. (1995) described another cysteine-generating mutation in the extracellular domain of FGFR3: a C-to-G transversion at nucleotide 746, which changed ser249 to cys. … (more)
Tavormina et al. (1995) described another cysteine-generating mutation in the extracellular domain of FGFR3: a C-to-G transversion at nucleotide 746, which changed ser249 to cys. The authors speculated that the unpaired cysteine residue in this region of the protein might result in formation of intermolecular disulfide bonds between 2 mutant FGFR3 monomers and thereby constitutively activate the receptor complex. Of the FGFR3 mutations identified by Cappellen et al. (1999) in epithelial tumors, the ser249-to-cys somatic mutation was the most common, affecting 5 of 9 bladder cancers (109800) and 3 of 3 cervical cancers (603956). Logie et al. (2005) identified a somatic S249C mutation in the FGFR3 gene in 5 seborrheic keratoses (182000). (less)
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Pathogenic
(May 01, 2005)
|
no assertion criteria provided
Method: literature only
|
KERATOSIS, SEBORRHEIC, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000038023.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Tavormina et al. (1995) described another cysteine-generating mutation in the extracellular domain of FGFR3: a C-to-G transversion at nucleotide 746, which changed ser249 to cys. … (more)
Tavormina et al. (1995) described another cysteine-generating mutation in the extracellular domain of FGFR3: a C-to-G transversion at nucleotide 746, which changed ser249 to cys. The authors speculated that the unpaired cysteine residue in this region of the protein might result in formation of intermolecular disulfide bonds between 2 mutant FGFR3 monomers and thereby constitutively activate the receptor complex. Of the FGFR3 mutations identified by Cappellen et al. (1999) in epithelial tumors, the ser249-to-cys somatic mutation was the most common, affecting 5 of 9 bladder cancers (109800) and 3 of 3 cervical cancers (603956). Logie et al. (2005) identified a somatic S249C mutation in the FGFR3 gene in 5 seborrheic keratoses (182000). (less)
|
|
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Pathogenic
(May 01, 2005)
|
no assertion criteria provided
Method: literature only
|
THANATOPHORIC DYSPLASIA, TYPE I
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000038020.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Tavormina et al. (1995) described another cysteine-generating mutation in the extracellular domain of FGFR3: a C-to-G transversion at nucleotide 746, which changed ser249 to cys. … (more)
Tavormina et al. (1995) described another cysteine-generating mutation in the extracellular domain of FGFR3: a C-to-G transversion at nucleotide 746, which changed ser249 to cys. The authors speculated that the unpaired cysteine residue in this region of the protein might result in formation of intermolecular disulfide bonds between 2 mutant FGFR3 monomers and thereby constitutively activate the receptor complex. Of the FGFR3 mutations identified by Cappellen et al. (1999) in epithelial tumors, the ser249-to-cys somatic mutation was the most common, affecting 5 of 9 bladder cancers (109800) and 3 of 3 cervical cancers (603956). Logie et al. (2005) identified a somatic S249C mutation in the FGFR3 gene in 5 seborrheic keratoses (182000). (less)
|
|
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Pathogenic
(May 01, 2005)
|
no assertion criteria provided
Method: literature only
|
CERVICAL CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000038021.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Tavormina et al. (1995) described another cysteine-generating mutation in the extracellular domain of FGFR3: a C-to-G transversion at nucleotide 746, which changed ser249 to cys. … (more)
Tavormina et al. (1995) described another cysteine-generating mutation in the extracellular domain of FGFR3: a C-to-G transversion at nucleotide 746, which changed ser249 to cys. The authors speculated that the unpaired cysteine residue in this region of the protein might result in formation of intermolecular disulfide bonds between 2 mutant FGFR3 monomers and thereby constitutively activate the receptor complex. Of the FGFR3 mutations identified by Cappellen et al. (1999) in epithelial tumors, the ser249-to-cys somatic mutation was the most common, affecting 5 of 9 bladder cancers (109800) and 3 of 3 cervical cancers (603956). Logie et al. (2005) identified a somatic S249C mutation in the FGFR3 gene in 5 seborrheic keratoses (182000). (less)
|
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Pathogenic
(Nov 18, 2018)
|
no assertion criteria provided
Method: clinical testing
|
thanatophoric dysplasia type 1
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000854615.1
First in ClinVar: Dec 07, 2018 Last updated: Dec 07, 2018 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965568.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Urinary bladder carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504978.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Papillary renal cell carcinoma, sporadic
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506422.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506424.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 13, 2016)
|
no assertion criteria provided
Method: literature only
|
Carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506423.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Transitional cell carcinoma of the bladder
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506421.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Squamous cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000506425.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 05, 2020)
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no assertion criteria provided
Method: clinical testing, in vivo
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Squamous Cell Lung Carcinoma
Affected status: yes
Allele origin:
somatic
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Faculté Pluridciplinaire Nador, Université Mohamed Premier
Accession: SCV001250917.1
First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Sex: male
Tissue: Liver metastasis Tumor
Result:
Percentage of variant in tissue sample = 26.23%
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951116.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Nov 29, 2021)
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no assertion criteria provided
Method: research
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See cases
Affected status: yes
Allele origin:
germline
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Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University
Accession: SCV003844085.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Clinical Features:
Skeletal dysplasia (present) , Coarctation of aorta (present) , Cerebellar hypoplasia (present)
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not provided
(-)
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no classification provided
Method: literature only
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Thanatophoric dysplasia type 1
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000086718.2
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022 |
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Comment:
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
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variation affecting protein function
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Bioinformatics dept., Datar Cancer Genetics Limited, India
Accession: SCV000584006.1
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Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP5,PP4,PP3.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Thanatophoric Dysplasia. | Adam MP | - | 2023 | PMID: 20301540 |
| Next-Generation Sequencing at High Sequencing Depth as a Tool to Study the Evolution of Metastasis Driven by Genetic Change Events of Lung Squamous Cell Carcinoma. | Mansour H | Frontiers in oncology | 2020 | DOI: 10.3389/fonc.2020.01215 |
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization. | Del Piccolo N | Biophysical journal | 2015 | PMID: 25606676 |
| FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. | Xue Y | Molecular genetics & genomic medicine | 2014 | PMID: 25614871 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Mutant fibroblast growth factor receptor 3 induces intracellular signaling and cellular transformation in a cell type- and mutation-specific manner. | di Martino E | Oncogene | 2009 | PMID: 19749790 |
| Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. | Qing J | The Journal of clinical investigation | 2009 | PMID: 19381019 |
| Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. | Tomlinson DC | Oncogene | 2007 | PMID: 17384684 |
| Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. | Logié A | Human molecular genetics | 2005 | PMID: 15772091 |
| Clinical and biochemical findings of a patient with thanatophoric dysplasia type I: additional finding of dicarboxylic aciduria. | Okajima K | The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association | 2002 | PMID: 11879084 |
| Sonographic and molecular diagnosis of thanatophoric dysplasia type I at 18 weeks of gestation. | De Biasio P | Prenatal diagnosis | 2000 | PMID: 11038465 |
| Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. | Cappellen D | Nature genetics | 1999 | PMID: 10471491 |
| Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. | Tavormina PL | Human molecular genetics | 1995 | PMID: 8589699 |
| http://docm.genome.wustl.edu/variants/ENST00000340107:c.746C>G | - | - | - | - |
| http://docm.genome.wustl.edu/variants/ENST00000352904:c.746C>G | - | - | - | - |
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Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
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Oncogenic
criteria provided, multiple submitters, no conflicts
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Feb 16, 2024 | RCV003758684.4 |
Submissions - Somatic
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Oncogenicity
Help
The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
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Oncogenic
(Feb 16, 2024)
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criteria provided, single submitter
Method: curation
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Cancer
Affected status: unknown
Allele origin:
somatic
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CIViC knowledgebase, Washington University School of Medicine
Accession: SCV004565363.1
First In ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Oncogenic
(Feb 16, 2024)
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criteria provided, single submitter
Method: curation
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Cancer
Affected status: unknown
Allele origin:
somatic
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Wagner Lab, Nationwide Children's Hospital
Accession: SCV005045671.2
|
Comment:
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 … (more)
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. (less)
|
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP5,PP4,PP3.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
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.
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| FGFR(3S249C) mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells. | Xie X | Experimental and therapeutic medicine | 2019 | PMID: 31316618 |
| Drug-sensitive FGFR3 mutations in lung adenocarcinoma. | Chandrani P | Annals of oncology : official journal of the European Society for Medical Oncology | 2017 | PMID: 27998968 |
| Effect of thanatophoric dysplasia type I mutations on FGFR3 dimerization. | Del Piccolo N | Biophysical journal | 2015 | PMID: 25606676 |
| Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma. | Liao RG | Cancer research | 2013 | PMID: 23786770 |
| Mutant fibroblast growth factor receptor 3 induces intracellular signaling and cellular transformation in a cell type- and mutation-specific manner. | di Martino E | Oncogene | 2009 | PMID: 19749790 |
| Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. | Qing J | The Journal of clinical investigation | 2009 | PMID: 19381019 |
| Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. | Tomlinson DC | Oncogene | 2007 | PMID: 17384684 |
| Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b. | Bernard-Pierrot I | Carcinogenesis | 2006 | PMID: 16338952 |
| https://civicdb.org/links/evidence/10386 | - | - | - | - |
| https://civicdb.org/links/evidence/4871 | - | - | - | - |
| https://civicdb.org/links/evidence/7306 | - | - | - | - |
| https://civicdb.org/links/evidence/7941 | - | - | - | - |
| https://civicdb.org/links/evidence/8642 | - | - | - | - |
| https://civicdb.org/links/evidence/8811 | - | - | - | - |
| https://civicdb.org/links/evidence/8853 | - | - | - | - |
| https://civicdb.org/links/evidence/8854 | - | - | - | - |
| https://civicdb.org/links/evidence/8855 | - | - | - | - |
| https://identifiers.org/civic.mpid:624 | - | - | - | - |
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Text-mined citations for rs121913483 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.