VCV000016332.87 - ClinVar

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

Germline

Classification

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.

(53)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 16332 Accession: VCV000016332.87

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p16.3 4: 1801837 (GRCh38) [ NCBI UCSC ] 4: 1803564 (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	Nov 24, 2024	Oct 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000142.5:c.742C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000133.1:p.Arg248Cys	missense
NM_001163213.1:c.742c>T
NM_001163213.2:c.742C>T	NP_001156685.1:p.Arg248Cys	missense
NM_001354809.2:c.742C>T	NP_001341738.1:p.Arg248Cys	missense
NM_001354810.2:c.742C>T	NP_001341739.1:p.Arg248Cys	missense
NM_022965.4:c.742C>T	NP_075254.1:p.Arg248Cys	missense
NR_148971.2:n.1017C>T		non-coding transcript variant
NC_000004.12:g.1801837C>T
NC_000004.11:g.1803564C>T
NG_012632.1:g.13526C>T
LRG_1021:g.13526C>T
LRG_1021t1:c.742C>T	LRG_1021p1:p.Arg248Cys
	P22607:p.Arg248Cys

... more HGVS ... less HGVS

Protein change

R248C

Other names

Canonical SPDI

NC_000004.12:1801836:C:T

Functional consequence Help The 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) Help The 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

ClinGen: CA126378 Genetic Testing Registry (GTR): GTR000568358 UniProtKB: P22607#VAR_004148 OMIM: 134934.0005 dbSNP: rs121913482 VarSome

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
Gene	OMIM	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.
Skeletal dysplasia with acanthosis nigricans	Pathogenic (1)	no assertion criteria provided	Sep 1, 2008	RCV000017733.37
Epidermal nevus	Pathogenic (2)	criteria provided, single submitter	Sep 22, 2023	RCV000017734.16
Seborrheic keratosis	Pathogenic (1)	no assertion criteria provided	Sep 1, 2008	RCV000017735.14
Thanatophoric dysplasia type 1	Pathogenic (15)	criteria provided, multiple submitters, no conflicts	Oct 23, 2024	RCV000017731.58
Multiple myeloma	Pathogenic/Likely pathogenic (2)	no assertion criteria provided	May 31, 2016	RCV000017732.16
not provided	Pathogenic (12)	criteria provided, multiple submitters, no conflicts	Jan 11, 2024	RCV000327823.53
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000420041.9
Carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 13, 2016	RCV000425165.9
Bell-shaped thorax Bowed humerus Disproportionate short-limb short stature Femoral bowing Growth delay Lethal short-limbed short stature Lower limb undergrowth Narrow chest Short ribs Short stature Skeletal dysplasia Small for gestational age Upper limb undergrowth	Pathogenic (1)	criteria provided, single submitter	May 8, 2015	RCV000414822.10
Transitional cell carcinoma of the bladder	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000425802.9
Squamous cell lung carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000432622.9
Squamous cell carcinoma of the head and neck	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000443913.9
Achondroplasia Camptodactyly-tall stature-scoliosis-hearing loss syndrome Carcinoma of colon Cervical cancer Crouzon syndrome-acanthosis nigricans syndrome Epidermal nevus Hypochondroplasia Levy-Hollister syndrome Malignant tumor of testis Malignant tumor of urinary bladder Muenke syndrome Severe achondroplasia-developmental delay-acanthosis nigricans syndrome Thanatophoric dysplasia type 1 Thanatophoric dysplasia, type 2	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763118.10
Hamartoma	Pathogenic (1)	criteria provided, single submitter	-	RCV001526641.10
Cervical cancer	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2016	RCV001196297.10
FGFR3-related disorder	Pathogenic (2)	criteria provided, single submitter	Feb 1, 2022	RCV002243648.12
Achondroplasia	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV001804739.14
Connective tissue disorder	Pathogenic (1)	criteria provided, single submitter	Jul 5, 2022	RCV002276552.10
FGFR3-related chondrodysplasia	Pathogenic (1)	criteria provided, single submitter	Mar 5, 2022	RCV001849270.11
Thanatophoric dysplasia, type 2	Pathogenic (1)	criteria provided, single submitter	-	RCV003388567.2
See cases	Pathogenic (1)	no assertion criteria provided	Jun 30, 2021	RCV003155030.8
Malignant tumor of urinary bladder	Pathogenic (1)	no assertion criteria provided	-	RCV003332082.2
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.
Pathogenic (May 08, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bell-shaped thorax Bowed humerus Disproportionate short-limb short stature Femoral bowing Growth delay Lethal short-limbed short stature Lower limb undergrowth Narrow chest Short ribs Short stature Skeletal dysplasia Small for gestational age Upper limb undergrowth Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492884.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV000893663.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (May 10, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450204.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 2
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cervical cancer Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366881.2 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Comment: This variant was classified as: Pathogenic.
Pathogenic (Jul 16, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000603712.5 First in ClinVar: Sep 30, 2017 Last updated: Jan 08, 2022	Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Achondroplasia Affected status: yes Allele origin: de novo	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002053885.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Pathogenic (Mar 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FGFR3-related chondrodysplasia Affected status: yes Allele origin: germline	DASA Accession: SCV002107095.2 First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022	Publications: PubMed (5) PubMed: 1908846‚ 25606676‚ 10696568‚ 7773297‚ 11241532 Comment: 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) … (more) 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. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Feb 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	FGFR3-related disorder Affected status: yes Allele origin: de novo	Daryl Scott Lab, Baylor College of Medicine Accession: SCV002515325.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Publications: PubMed (1) PubMed: 36474027 Number of individuals with the variant: 1
Pathogenic (Aug 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thanatophoric dysplasia type 1 Affected status: unknown Allele origin: maternal	Daryl Scott Lab, Baylor College of Medicine Accession: SCV002567938.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022	Publications: PubMed (1) PubMed: 36135330 Number of individuals with the variant: 1
Pathogenic (Mar 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thanatophoric dysplasia type 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000854614.2 First in ClinVar: Dec 06, 2016 Last updated: Mar 11, 2023
Pathogenic (Jan 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: de novo	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004025948.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thanatophoric dysplasia, type 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004100377.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Macrocephaly (present) , Hypertelorism (present) , Bell-shaped thorax (present) , Protuberant abdomen (present) , Limb undergrowth (present) , Lethal short-limbed short stature (present) , Skeletal … (more) Macrocephaly (present) , Hypertelorism (present) , Bell-shaped thorax (present) , Protuberant abdomen (present) , Limb undergrowth (present) , Lethal short-limbed short stature (present) , Skeletal dysplasia (present) , Disproportionate short-limb short stature (present) (less)
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Thanatophoric dysplasia type 1 Affected status: yes Allele origin: germline	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV004123085.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023
Pathogenic (Jun 22, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thanatophoric dysplasia type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Shanghai First Maternity and Infant Hospital, Tongji University Accession: SCV000282235.1 First in ClinVar: Jul 25, 2016 Last updated: Jul 25, 2016	Publications: PubMed (1) PubMed: 7773297 Comment: 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 … (more) 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 (less) Age: 20-29 weeks gestation Sex: female Ethnicity/Population group: Han Chinese Geographic origin: Southern Han Chinese Method: PCR and Sanger Sequencing
Pathogenic (Aug 13, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000334262.4 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 7773297 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FGFR3 http://www.ncbi.nlm.nih.gov/book… http://www.ncbi.nlm.nih.gov/books/NBK1366/ Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Dec 08, 2016)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Thanatophoric dysplasia type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001430109.1 First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020	Clinical Features: Skeletal dysplasia (present) Sex: female Tissue: blood
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hamartoma Affected status: yes Allele origin: somatic	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001737072.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021
Pathogenic (Mar 13, 2020)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001832516.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 Comment: Patient analyzed with Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel
Pathogenic (Dec 05, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329627.5 First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019	Comment: 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 … (more) 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) (less)
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Achondroplasia Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002516366.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Jul 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Connective tissue disorder Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002566636.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thanatophoric dysplasia type 1 Affected status: unknown Allele origin: unknown	Genomic Medicine Lab, University of California San Francisco Study: CSER Accession: SCV002576369.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022
Pathogenic (Oct 20, 2016)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Thanatophoric dysplasia, type I Affected status: yes Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000328407.2 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 Comment: Clinical Testing	Number of individuals with the variant: 1
Pathogenic (Jul 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thanatophoric dysplasia type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV003920966.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Method: Exome sequencing
Pathogenic (Sep 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Epidermal nevus Affected status: yes Allele origin: somatic	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004176920.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002023065.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Sep 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thanatophoric dysplasia type 1 Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV004239071.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Publications: PubMed (8) PubMed: 20420824‚ 22045636‚ 25606676‚ 25614871‚ 7773297‚ 8640234‚ 9438390‚ 9677066 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 11, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001389479.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 7773297‚ 10696568‚ 11241532‚ 1908846‚ 25606676 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 19, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Achondroplasia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004803862.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (2) PubMed: 29593476‚ 31299979 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Achondroplasia Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804902.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Sep 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197924.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Aug 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001962549.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Oct 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thanatophoric dysplasia type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV005375478.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Clinical Features: Abnormal thorax morphology (present) , Short long bone (present) , Short femur (present) , Lethal skeletal dysplasia (present) , Distal shortening of limbs (present) , … (more) Abnormal thorax morphology (present) , Short long bone (present) , Short femur (present) , Lethal skeletal dysplasia (present) , Distal shortening of limbs (present) , Lethal short-limbed short stature (present) (less)
Pathogenic (Oct 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thanatophoric dysplasia type 1 Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399782.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (5) PubMed: 16501574‚ 18000976‚ 24864036‚ 25614871‚ 26740388 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with autosomal dominant skeletal dysplasias (OMIM). Additionally, autosomal recessive and dominant CATSHL syndrome (MIM#610474), is suspected to be due to variants with a loss of function, and dominant negative mechanism, respectively (PMID: 25614871, 24864036). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals with Muenke syndrome have been shown to inherit pathogenic variants from an asymptomatic parent (PMID: 26740388, 18000976). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a wide range of clinical symptoms with variable expressivity in LADD and Muenke syndrome patients, even within the same family (PMID: 26740388, 16501574). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified many times as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Sep 01, 2008)	no assertion criteria provided Method: literature only	NEVUS, EPIDERMAL, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000038012.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (9) PubMed: 7773297‚ 8858131‚ 9677066‚ 10073901‚ 12833394‚ 16841094‚ 18642369‚ 11529856‚ 15772091 Comment on evidence: Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a … (more) Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a C-to-T transition at nucleotide 742 in 22 and a ser371-to-cys mutation (134934.0006) in 1. Both of these mutations were in the extracellular region of the FGFR3 protein. Although type II thanatophoric dysplasia (187601) cases have been found to have a single recurrent K650E change (134934.0004), type I cases have different mutations affecting either the extracellular or intracellular domains of FGFR3. However, mutations in the FGFR3 gene were identified in only approximately 60% of the type I TD cases. These findings, and the range of symptoms observed, suggested that type I TD is heterogeneous in genetic background. Pokharel et al. (1996) described a Japanese type I TD patient followed for more than 9 years. They found that the patient had the arg248-to-cys mutation as did 4 other Japanese cases of type I TD. No association was found with the ser371-to-cys mutation. The R248C mutation was the most frequent cause of thanatophoric dysplasia in the 91 cases reviewed in detail by Wilcox et al. (1998), occurring in almost 50% (45) of the cases. Although prenatal diagnosis of TD had been accomplished by ultrasonography in the second trimester, it was not always possible to distinguish between TD and other osteochondrodysplasias in utero. Using restriction enzyme analysis, Sawai et al. (1999) identified the common 742C-T mutation in the FGFR3 gene in a fetus at 27 weeks' gestation. Hyland et al. (2003) described a woman who was a somatic and germline mosaic for the R248C missense mutation in FGFR3. She had disproportionate short stature, rhizomelic limb shortening, and other skeletal features accompanied by widespread acanthosis nigricans. These features were clearly different from those seen in thanatophoric dysplasia or other skeletal dysplasias. Her only pregnancy ended in delivery of a fetus with lethal short-limb dwarfism and pulmonary hyperplasia, strongly suggestive of thanatophoric dysplasia. Nevus, Epidermal, Somatic Hafner et al. (2006) analyzed the FGFR3 gene in 39 common epidermal nevi (162900) from 33 patients and identified the R248C mutation in 10 of 11 mutation-positive patients; In 4 patients tested, FGFR3 mutations were not found in adjacent, histologically normal skin. Hafner et al. (2006) concluded that a large proportion of epidermal nevi are caused by mosaicism of activating FGFR3 mutations in the human epidermis secondary to a postzygotic mutation in early embryonic development, and that the R248C mutation appears to be a hotspot for FGFR3 mutations in epidermal nevi. Garcia-Vargas et al. (2008) reported a 5-year-old Mexican girl with epidermal nevi, mental impairment, and seizures in whom they identified somatic mosaicism for a heterozygous R248C mutation in lesional skin and lymphocytes but not in normal skin. She had generalized linear epidermal nevi with a soft, velvety texture following the lines of Blaschko, and sparing the scalp, palms, and soles. She had delayed development, and brain CT showed cortical and subcortical atrophy, a subdural hygroma, and hypoplasia of the corpus callosum. The findings suggested that the mutation involved the skin, brain, and blood cells. Although there were no skeletal anomalies, Garcia-Vargas et al. (2008) considered the phenotype to be consistent with a mosaic manifestation of TD type I, but also proposed a preliminary designation of 'FGFR3 epidermal nevus syndrome.' Multiple Myeloma, Somatic Intini et al. (2001) investigated FGFR3 mutations in a series of 53 multiple myeloma (254500) cases, 11 of which had a t(4;14) translocation and FGFR3 overexpression. The arg248-to-cys mutation was found in 1 case with t(4;14). Intini et al. (2001) concluded that FGFR3 mutations occur in only a small fraction of multiple myeloma cases with t(4;14). Keratosis, Seborrheic, Somatic Logie et al. (2005) identified a somatic R248C mutation in the FGFR3 gene in 5 seborrheic keratoses (182000). (less)
Pathogenic (Sep 01, 2008)	no assertion criteria provided Method: literature only	KERATOSIS, SEBORRHEIC, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000038013.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (9) PubMed: 7773297‚ 8858131‚ 9677066‚ 10073901‚ 12833394‚ 16841094‚ 18642369‚ 11529856‚ 15772091 Comment on evidence: Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a … (more) Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a C-to-T transition at nucleotide 742 in 22 and a ser371-to-cys mutation (134934.0006) in 1. Both of these mutations were in the extracellular region of the FGFR3 protein. Although type II thanatophoric dysplasia (187601) cases have been found to have a single recurrent K650E change (134934.0004), type I cases have different mutations affecting either the extracellular or intracellular domains of FGFR3. However, mutations in the FGFR3 gene were identified in only approximately 60% of the type I TD cases. These findings, and the range of symptoms observed, suggested that type I TD is heterogeneous in genetic background. Pokharel et al. (1996) described a Japanese type I TD patient followed for more than 9 years. They found that the patient had the arg248-to-cys mutation as did 4 other Japanese cases of type I TD. No association was found with the ser371-to-cys mutation. The R248C mutation was the most frequent cause of thanatophoric dysplasia in the 91 cases reviewed in detail by Wilcox et al. (1998), occurring in almost 50% (45) of the cases. Although prenatal diagnosis of TD had been accomplished by ultrasonography in the second trimester, it was not always possible to distinguish between TD and other osteochondrodysplasias in utero. Using restriction enzyme analysis, Sawai et al. (1999) identified the common 742C-T mutation in the FGFR3 gene in a fetus at 27 weeks' gestation. Hyland et al. (2003) described a woman who was a somatic and germline mosaic for the R248C missense mutation in FGFR3. She had disproportionate short stature, rhizomelic limb shortening, and other skeletal features accompanied by widespread acanthosis nigricans. These features were clearly different from those seen in thanatophoric dysplasia or other skeletal dysplasias. Her only pregnancy ended in delivery of a fetus with lethal short-limb dwarfism and pulmonary hyperplasia, strongly suggestive of thanatophoric dysplasia. Nevus, Epidermal, Somatic Hafner et al. (2006) analyzed the FGFR3 gene in 39 common epidermal nevi (162900) from 33 patients and identified the R248C mutation in 10 of 11 mutation-positive patients; In 4 patients tested, FGFR3 mutations were not found in adjacent, histologically normal skin. Hafner et al. (2006) concluded that a large proportion of epidermal nevi are caused by mosaicism of activating FGFR3 mutations in the human epidermis secondary to a postzygotic mutation in early embryonic development, and that the R248C mutation appears to be a hotspot for FGFR3 mutations in epidermal nevi. Garcia-Vargas et al. (2008) reported a 5-year-old Mexican girl with epidermal nevi, mental impairment, and seizures in whom they identified somatic mosaicism for a heterozygous R248C mutation in lesional skin and lymphocytes but not in normal skin. She had generalized linear epidermal nevi with a soft, velvety texture following the lines of Blaschko, and sparing the scalp, palms, and soles. She had delayed development, and brain CT showed cortical and subcortical atrophy, a subdural hygroma, and hypoplasia of the corpus callosum. The findings suggested that the mutation involved the skin, brain, and blood cells. Although there were no skeletal anomalies, Garcia-Vargas et al. (2008) considered the phenotype to be consistent with a mosaic manifestation of TD type I, but also proposed a preliminary designation of 'FGFR3 epidermal nevus syndrome.' Multiple Myeloma, Somatic Intini et al. (2001) investigated FGFR3 mutations in a series of 53 multiple myeloma (254500) cases, 11 of which had a t(4;14) translocation and FGFR3 overexpression. The arg248-to-cys mutation was found in 1 case with t(4;14). Intini et al. (2001) concluded that FGFR3 mutations occur in only a small fraction of multiple myeloma cases with t(4;14). Keratosis, Seborrheic, Somatic Logie et al. (2005) identified a somatic R248C mutation in the FGFR3 gene in 5 seborrheic keratoses (182000). (less)
Pathogenic (Sep 01, 2008)	no assertion criteria provided Method: literature only	THANATOPHORIC DYSPLASIA, TYPE I Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000038009.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (9) PubMed: 7773297‚ 8858131‚ 9677066‚ 10073901‚ 12833394‚ 16841094‚ 18642369‚ 11529856‚ 15772091 Comment on evidence: Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a … (more) Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a C-to-T transition at nucleotide 742 in 22 and a ser371-to-cys mutation (134934.0006) in 1. Both of these mutations were in the extracellular region of the FGFR3 protein. Although type II thanatophoric dysplasia (187601) cases have been found to have a single recurrent K650E change (134934.0004), type I cases have different mutations affecting either the extracellular or intracellular domains of FGFR3. However, mutations in the FGFR3 gene were identified in only approximately 60% of the type I TD cases. These findings, and the range of symptoms observed, suggested that type I TD is heterogeneous in genetic background. Pokharel et al. (1996) described a Japanese type I TD patient followed for more than 9 years. They found that the patient had the arg248-to-cys mutation as did 4 other Japanese cases of type I TD. No association was found with the ser371-to-cys mutation. The R248C mutation was the most frequent cause of thanatophoric dysplasia in the 91 cases reviewed in detail by Wilcox et al. (1998), occurring in almost 50% (45) of the cases. Although prenatal diagnosis of TD had been accomplished by ultrasonography in the second trimester, it was not always possible to distinguish between TD and other osteochondrodysplasias in utero. Using restriction enzyme analysis, Sawai et al. (1999) identified the common 742C-T mutation in the FGFR3 gene in a fetus at 27 weeks' gestation. Hyland et al. (2003) described a woman who was a somatic and germline mosaic for the R248C missense mutation in FGFR3. She had disproportionate short stature, rhizomelic limb shortening, and other skeletal features accompanied by widespread acanthosis nigricans. These features were clearly different from those seen in thanatophoric dysplasia or other skeletal dysplasias. Her only pregnancy ended in delivery of a fetus with lethal short-limb dwarfism and pulmonary hyperplasia, strongly suggestive of thanatophoric dysplasia. Nevus, Epidermal, Somatic Hafner et al. (2006) analyzed the FGFR3 gene in 39 common epidermal nevi (162900) from 33 patients and identified the R248C mutation in 10 of 11 mutation-positive patients; In 4 patients tested, FGFR3 mutations were not found in adjacent, histologically normal skin. Hafner et al. (2006) concluded that a large proportion of epidermal nevi are caused by mosaicism of activating FGFR3 mutations in the human epidermis secondary to a postzygotic mutation in early embryonic development, and that the R248C mutation appears to be a hotspot for FGFR3 mutations in epidermal nevi. Garcia-Vargas et al. (2008) reported a 5-year-old Mexican girl with epidermal nevi, mental impairment, and seizures in whom they identified somatic mosaicism for a heterozygous R248C mutation in lesional skin and lymphocytes but not in normal skin. She had generalized linear epidermal nevi with a soft, velvety texture following the lines of Blaschko, and sparing the scalp, palms, and soles. She had delayed development, and brain CT showed cortical and subcortical atrophy, a subdural hygroma, and hypoplasia of the corpus callosum. The findings suggested that the mutation involved the skin, brain, and blood cells. Although there were no skeletal anomalies, Garcia-Vargas et al. (2008) considered the phenotype to be consistent with a mosaic manifestation of TD type I, but also proposed a preliminary designation of 'FGFR3 epidermal nevus syndrome.' Multiple Myeloma, Somatic Intini et al. (2001) investigated FGFR3 mutations in a series of 53 multiple myeloma (254500) cases, 11 of which had a t(4;14) translocation and FGFR3 overexpression. The arg248-to-cys mutation was found in 1 case with t(4;14). Intini et al. (2001) concluded that FGFR3 mutations occur in only a small fraction of multiple myeloma cases with t(4;14). Keratosis, Seborrheic, Somatic Logie et al. (2005) identified a somatic R248C mutation in the FGFR3 gene in 5 seborrheic keratoses (182000). (less)
Pathogenic (Sep 01, 2008)	no assertion criteria provided Method: literature only	MULTIPLE MYELOMA, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000038010.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (9) PubMed: 7773297‚ 8858131‚ 9677066‚ 10073901‚ 12833394‚ 16841094‚ 18642369‚ 11529856‚ 15772091 Comment on evidence: Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a … (more) Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a C-to-T transition at nucleotide 742 in 22 and a ser371-to-cys mutation (134934.0006) in 1. Both of these mutations were in the extracellular region of the FGFR3 protein. Although type II thanatophoric dysplasia (187601) cases have been found to have a single recurrent K650E change (134934.0004), type I cases have different mutations affecting either the extracellular or intracellular domains of FGFR3. However, mutations in the FGFR3 gene were identified in only approximately 60% of the type I TD cases. These findings, and the range of symptoms observed, suggested that type I TD is heterogeneous in genetic background. Pokharel et al. (1996) described a Japanese type I TD patient followed for more than 9 years. They found that the patient had the arg248-to-cys mutation as did 4 other Japanese cases of type I TD. No association was found with the ser371-to-cys mutation. The R248C mutation was the most frequent cause of thanatophoric dysplasia in the 91 cases reviewed in detail by Wilcox et al. (1998), occurring in almost 50% (45) of the cases. Although prenatal diagnosis of TD had been accomplished by ultrasonography in the second trimester, it was not always possible to distinguish between TD and other osteochondrodysplasias in utero. Using restriction enzyme analysis, Sawai et al. (1999) identified the common 742C-T mutation in the FGFR3 gene in a fetus at 27 weeks' gestation. Hyland et al. (2003) described a woman who was a somatic and germline mosaic for the R248C missense mutation in FGFR3. She had disproportionate short stature, rhizomelic limb shortening, and other skeletal features accompanied by widespread acanthosis nigricans. These features were clearly different from those seen in thanatophoric dysplasia or other skeletal dysplasias. Her only pregnancy ended in delivery of a fetus with lethal short-limb dwarfism and pulmonary hyperplasia, strongly suggestive of thanatophoric dysplasia. Nevus, Epidermal, Somatic Hafner et al. (2006) analyzed the FGFR3 gene in 39 common epidermal nevi (162900) from 33 patients and identified the R248C mutation in 10 of 11 mutation-positive patients; In 4 patients tested, FGFR3 mutations were not found in adjacent, histologically normal skin. Hafner et al. (2006) concluded that a large proportion of epidermal nevi are caused by mosaicism of activating FGFR3 mutations in the human epidermis secondary to a postzygotic mutation in early embryonic development, and that the R248C mutation appears to be a hotspot for FGFR3 mutations in epidermal nevi. Garcia-Vargas et al. (2008) reported a 5-year-old Mexican girl with epidermal nevi, mental impairment, and seizures in whom they identified somatic mosaicism for a heterozygous R248C mutation in lesional skin and lymphocytes but not in normal skin. She had generalized linear epidermal nevi with a soft, velvety texture following the lines of Blaschko, and sparing the scalp, palms, and soles. She had delayed development, and brain CT showed cortical and subcortical atrophy, a subdural hygroma, and hypoplasia of the corpus callosum. The findings suggested that the mutation involved the skin, brain, and blood cells. Although there were no skeletal anomalies, Garcia-Vargas et al. (2008) considered the phenotype to be consistent with a mosaic manifestation of TD type I, but also proposed a preliminary designation of 'FGFR3 epidermal nevus syndrome.' Multiple Myeloma, Somatic Intini et al. (2001) investigated FGFR3 mutations in a series of 53 multiple myeloma (254500) cases, 11 of which had a t(4;14) translocation and FGFR3 overexpression. The arg248-to-cys mutation was found in 1 case with t(4;14). Intini et al. (2001) concluded that FGFR3 mutations occur in only a small fraction of multiple myeloma cases with t(4;14). Keratosis, Seborrheic, Somatic Logie et al. (2005) identified a somatic R248C mutation in the FGFR3 gene in 5 seborrheic keratoses (182000). (less)
Pathogenic (Sep 01, 2008)	no assertion criteria provided Method: literature only	SKELETAL DYSPLASIA WITH ACANTHOSIS NIGRICANS Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000038011.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024	Publications: PubMed (9) PubMed: 7773297‚ 8858131‚ 9677066‚ 10073901‚ 12833394‚ 16841094‚ 18642369‚ 11529856‚ 15772091 Comment on evidence: Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a … (more) Thanatophoric Dysplasia, Type I Of 39 individuals with type I thanatophoric dysplasia (TD1; 187600), Tavormina et al. (1995) found an arg248-to-cys mutation resulting from a C-to-T transition at nucleotide 742 in 22 and a ser371-to-cys mutation (134934.0006) in 1. Both of these mutations were in the extracellular region of the FGFR3 protein. Although type II thanatophoric dysplasia (187601) cases have been found to have a single recurrent K650E change (134934.0004), type I cases have different mutations affecting either the extracellular or intracellular domains of FGFR3. However, mutations in the FGFR3 gene were identified in only approximately 60% of the type I TD cases. These findings, and the range of symptoms observed, suggested that type I TD is heterogeneous in genetic background. Pokharel et al. (1996) described a Japanese type I TD patient followed for more than 9 years. They found that the patient had the arg248-to-cys mutation as did 4 other Japanese cases of type I TD. No association was found with the ser371-to-cys mutation. The R248C mutation was the most frequent cause of thanatophoric dysplasia in the 91 cases reviewed in detail by Wilcox et al. (1998), occurring in almost 50% (45) of the cases. Although prenatal diagnosis of TD had been accomplished by ultrasonography in the second trimester, it was not always possible to distinguish between TD and other osteochondrodysplasias in utero. Using restriction enzyme analysis, Sawai et al. (1999) identified the common 742C-T mutation in the FGFR3 gene in a fetus at 27 weeks' gestation. Hyland et al. (2003) described a woman who was a somatic and germline mosaic for the R248C missense mutation in FGFR3. She had disproportionate short stature, rhizomelic limb shortening, and other skeletal features accompanied by widespread acanthosis nigricans. These features were clearly different from those seen in thanatophoric dysplasia or other skeletal dysplasias. Her only pregnancy ended in delivery of a fetus with lethal short-limb dwarfism and pulmonary hyperplasia, strongly suggestive of thanatophoric dysplasia. Nevus, Epidermal, Somatic Hafner et al. (2006) analyzed the FGFR3 gene in 39 common epidermal nevi (162900) from 33 patients and identified the R248C mutation in 10 of 11 mutation-positive patients; In 4 patients tested, FGFR3 mutations were not found in adjacent, histologically normal skin. Hafner et al. (2006) concluded that a large proportion of epidermal nevi are caused by mosaicism of activating FGFR3 mutations in the human epidermis secondary to a postzygotic mutation in early embryonic development, and that the R248C mutation appears to be a hotspot for FGFR3 mutations in epidermal nevi. Garcia-Vargas et al. (2008) reported a 5-year-old Mexican girl with epidermal nevi, mental impairment, and seizures in whom they identified somatic mosaicism for a heterozygous R248C mutation in lesional skin and lymphocytes but not in normal skin. She had generalized linear epidermal nevi with a soft, velvety texture following the lines of Blaschko, and sparing the scalp, palms, and soles. She had delayed development, and brain CT showed cortical and subcortical atrophy, a subdural hygroma, and hypoplasia of the corpus callosum. The findings suggested that the mutation involved the skin, brain, and blood cells. Although there were no skeletal anomalies, Garcia-Vargas et al. (2008) considered the phenotype to be consistent with a mosaic manifestation of TD type I, but also proposed a preliminary designation of 'FGFR3 epidermal nevus syndrome.' Multiple Myeloma, Somatic Intini et al. (2001) investigated FGFR3 mutations in a series of 53 multiple myeloma (254500) cases, 11 of which had a t(4;14) translocation and FGFR3 overexpression. The arg248-to-cys mutation was found in 1 case with t(4;14). Intini et al. (2001) concluded that FGFR3 mutations occur in only a small fraction of multiple myeloma cases with t(4;14). Keratosis, Seborrheic, Somatic Logie et al. (2005) identified a somatic R248C mutation in the FGFR3 gene in 5 seborrheic keratoses (182000). (less)
Pathogenic (Mar 29, 2024)	no assertion criteria provided Method: clinical testing	FGFR3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004105863.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: 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 … (more) The FGFR3 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Cys. This variant has repeatedly been reported to be causative for autosomal dominant thanatophoric dysplasia (Tavormina et al. 1995. PubMed ID: 7773297; Camera et al. 2001. PubMed ID: 11754059; Castori et al. 2013. PubMed ID: 24038754; Table S3b, Wojcik et al. 2019. PubMed ID: 31395954; Table S1, Maddirevula et al. 2018. PubMed ID: 29620724). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000505529.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000340107:c.742C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Multiple myeloma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506416.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000352904:c.742C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Squamous cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506418.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000352904:c.742C>T
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: SCV000506420.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 10471491 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000352904:c.742C>T
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: SCV000506419.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000352904:c.742C>T
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: SCV000506417.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000352904:c.742C>T
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001955168.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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: SCV001974802.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Jan 30, 2022)	no assertion criteria provided Method: clinical testing	Thanatophoric dysplasia type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital Accession: SCV002072477.1 First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022	Publications: PubMed (1) PubMed: 7773297 Comment: 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 … (more) 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. (less) Ethnicity/Population group: South East Asian Geographic origin: India
Pathogenic (Jun 30, 2021)	no assertion criteria provided Method: research	See cases Affected status: yes Allele origin: germline	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University Accession: SCV003844074.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Clinical Features: Abnormality of the skeletal system (present)
Pathogenic (Apr 01, 2023)	no assertion criteria provided Method: clinical testing	Thanatophoric dysplasia type 1 Affected status: yes Allele origin: germline	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) Accession: SCV003927941.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023
Pathogenic (-)	no assertion criteria provided Method: research	Malignant tumor of urinary bladder Affected status: yes Allele origin: somatic	Laboratory of Urology, Hospital Clinic de Barcelona Accession: SCV004040569.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
not provided (-)	no classification provided Method: literature only	Thanatophoric dysplasia type 1 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086717.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301540 BookShelf: NBK1366 BookShelf: NBK1366
click to load more click to collapse

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with autosomal dominant skeletal dysplasias (OMIM). Additionally, autosomal recessive and dominant CATSHL syndrome (MIM#610474), is suspected to be due to variants with a loss of function, and dominant negative mechanism, respectively (PMID: 25614871, 24864036). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals with Muenke syndrome have been shown to inherit pathogenic variants from an asymptomatic parent (PMID: 26740388, 18000976). (I) 0115 - Variants in this gene are known to have variable expressivity. There is a wide range of clinical symptoms with variable expressivity in LADD and Muenke syndrome patients, even within the same family (PMID: 26740388, 16501574). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified many times as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The FGFR3 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Cys. This variant has repeatedly been reported to be causative for autosomal dominant thanatophoric dysplasia (Tavormina et al. 1995. PubMed ID: 7773297; Camera et al. 2001. PubMed ID: 11754059; Castori et al. 2013. PubMed ID: 24038754; Table S3b, Wojcik et al. 2019. PubMed ID: 31395954; Table S1, Maddirevula et al. 2018. PubMed ID: 29620724). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

Comment:

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.

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.
variation affecting protein function (VariO:0003)			Shanghai First Maternity and Infant Hospital, Tongji University Accession: SCV000282235.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations.	Belanger Deloge R	European journal of human genetics : EJHG	2023	PMID: 36474027
Thanatophoric Dysplasia.	Adam MP	-	2023	PMID: 20301540
Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus.	Sy MR	American journal of medical genetics. Part A	2022	PMID: 36135330
Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases.	Liu Y	Diagnostic pathology	2019	PMID: 31299979
Novel and Recurrent Mutations in the FGFR3 Gene and Double Heterozygosity Cases in a Cohort of Brazilian Patients with Skeletal Dysplasia.	Gomes MES	Molecular syndromology	2018	PMID: 29593476
Muenke syndrome: An international multicenter natural history study.	Kruszka P	American journal of medical genetics. Part A	2016	PMID: 26740388
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
A novel homozygous mutation in FGFR3 causes tall stature, severe lateral tibial deviation, scoliosis, hearing impairment, camptodactyly, and arachnodactyly.	Makrythanasis P	Human mutation	2014	PMID: 24864036
Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias.	Foldynova-Trantirkova S	Human mutation	2012	PMID: 22045636
FGFR3 mutation affects cell growth, apoptosis and attachment in keratinocytes.	Hafner C	Experimental cell research	2010	PMID: 20420824
An epidermal nevus syndrome with cerebral involvement caused by a mosaic FGFR3 mutation.	García-Vargas A	American journal of medical genetics. Part A	2008	PMID: 18642369
Muenke syndrome (FGFR3-related craniosynostosis): expansion of the phenotype and review of the literature.	Doherty ES	American journal of medical genetics. Part A	2007	PMID: 18000976
Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi.	Hafner C	The Journal of clinical investigation	2006	PMID: 16841094
Mutations in different components of FGF signaling in LADD syndrome.	Rohmann E	Nature genetics	2006	PMID: 16501574
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
Somatic and germline mosaicism for a R248C missense mutation in FGFR3, resulting in a skeletal dysplasia distinct from thanatophoric dysplasia.	Hyland VJ	American journal of medical genetics. Part A	2003	PMID: 12833394
Analysis of FGFR3 gene mutations in multiple myeloma patients with t(4;14).	Intini D	British journal of haematology	2001	PMID: 11529856
Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia.	Chen CP	Prenatal diagnosis	2001	PMID: 11241532
The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans.	Vajo Z	Endocrine reviews	2000	PMID: 10696568
Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas.	Cappellen D	Nature genetics	1999	PMID: 10471491
Prenatal diagnosis of thanatophoric dysplasia by mutational analysis of the fibroblast growth factor receptor 3 gene and a proposed correction of previously published PCR results.	Sawai H	Prenatal diagnosis	1999	PMID: 10073901
Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia.	Wilcox WR	American journal of medical genetics	1998	PMID: 9677066
Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I.	d'Avis PY	Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research	1998	PMID: 9438390
Japanese cases of type 1 thanatophoric dysplasia exclusively carry a C to T transition at nucleotide 742 of the fibroblast growth factor receptor 3 gene.	Pokharel RK	Biochemical and biophysical research communications	1996	PMID: 8858131
Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia.	Naski MC	Nature genetics	1996	PMID: 8640234
Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3.	Tavormina PL	Nature genetics	1995	PMID: 7773297
Effects of 3-aminobenzamide on induction of multiorgan carcinogenesis by N-nitrosobis(2-hydroxypropyl)amine in hamsters.	Tsujiuchi T	Japanese journal of cancer research : Gann	1991	PMID: 1908846
http://docm.genome.wustl.edu/variants/ENST00000340107:c.742C>T	-	-	-	-
http://docm.genome.wustl.edu/variants/ENST00000352904:c.742C>T	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FGFR3	-	-	-	-
click to load more click to collapse

Text-mined citations for rs121913482 ...

These 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

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913482 ...