4-1801837-C-T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000142.5(FGFR3):c.742C>T(p.Arg248Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R248R) has been classified as Likely benign.
Frequency
Consequence
NM_000142.5 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- achondroplasiaInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- Crouzon syndrome-acanthosis nigricans syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
- hypochondroplasiaInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
- lacrimoauriculodentodigital syndrome 2Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
- Muenke syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
- thanatophoric dysplasia type 1Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, ClinGen
- thanatophoric dysplasia type 2Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
- camptodactyly-tall stature-scoliosis-hearing loss syndromeInheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
- severe achondroplasia-developmental delay-acanthosis nigricans syndromeInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
- isolated brachycephalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- isolated plagiocephalyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- LADD syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- LADD syndrome 1Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000142.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FGFR3 | NM_000142.5 | MANE Select | c.742C>T | p.Arg248Cys | missense splice_region | Exon 7 of 18 | NP_000133.1 | ||
| FGFR3 | NM_001163213.2 | c.742C>T | p.Arg248Cys | missense splice_region | Exon 7 of 18 | NP_001156685.1 | |||
| FGFR3 | NM_001354809.2 | c.742C>T | p.Arg248Cys | missense splice_region | Exon 7 of 18 | NP_001341738.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FGFR3 | ENST00000440486.8 | TSL:5 MANE Select | c.742C>T | p.Arg248Cys | missense splice_region | Exon 7 of 18 | ENSP00000414914.2 | ||
| FGFR3 | ENST00000481110.7 | TSL:1 | c.742C>T | p.Arg248Cys | missense splice_region | Exon 7 of 17 | ENSP00000420533.2 | ||
| FGFR3 | ENST00000352904.6 | TSL:1 | c.742C>T | p.Arg248Cys | missense splice_region | Exon 6 of 15 | ENSP00000231803.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 38
GnomAD4 genome
ClinVar
Submissions by phenotype
Thanatophoric dysplasia type 1 Pathogenic:16Other:1
The variant is not observed in the gnomAD v4.0.0 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25606676). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.85 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.62 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016332 /PMID: 7773297). The variant has been previously reported as de novo in a similarly affected individual (ClinVar ID: SCV000282235.1). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22106050, 25614871, 7773297, 9677066; ClinVar ID: SCV000282235.1, SCV001430109.1). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 22106050, 7773297). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (both v2 and v3); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar; Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change; This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). Additional information: Variant is predicted to result in a missense amino acid change from arginine to cysteine; This variant is heterozygous; This gene is associated with both recessive and dominant disease (OMIM); Variant is not located in an established domain, motif, hotspot or informative constraint region; Gain of function is a known mechanism of disease in this gene and is associated with autosomal dominant skeletal dysplasias (OMIM). Autosomal recessive and dominant CATSHL syndrome (MIM#610474) are suspected to be due to variants resulting in a loss of function and dominant negative mechanism, respectively (PMID: 25614871, 24864036); 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); 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).
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.
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
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.
The missense variant c.742C>Tp.Arg248Cys in FGFR3 gene has been observed in heterozygous state in multiple individuals with thanatophoric dysplasia Xue et. al., 2014; Hylandet. al., 2003; Chen et. al., 2001. Experimental studies have shown that this missense change affects FGFR3 function Del Piccolo et. al., 2015. The observed variant is absent in gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic multiple submitters. Multiple lines of computational evidence Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Arg248Cys in FGFR3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 248 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
not provided Pathogenic:13
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)
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.
FGFR3: PS2:Very Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
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.
Achondroplasia Pathogenic:5
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.
FGFR3-related chondrodysplasia Pathogenic:2
The FGFR3 c.742C>T p.(Arg248Cys) missense variant is one of the most common variants reported in individuals with thanatophoric dysplasia and has been reported in over 100 cases, including in a de novo and mosaic state (PMID: 25614871; 12833394; 32360156; 33942288). It has also been reported in at least one individual with a clinical phenotype of achondroplasia with no mosaicism detected in blood or buccal mucosal cells (PMID: 11754059). The p.Arg248Cys variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest this variant may impact the gene or gene product, and functional studies have confirmed it results in FGFR3 activation (PMID: 19088846). This variant has a consensus pathogenic classification in ClinVar. Based on the available evidence, the c.742C>T p.(Arg248Cys) variant is classified as pathogenic for FGFR3 chondrodysplasias.
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.
See cases Pathogenic:2
ACMG categories: PS1,PS2,PS4,PM1,PM2
Epidermal nevus Pathogenic:2
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.
FGFR3-related disorder Pathogenic:2
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.
Seborrheic keratosis Pathogenic:1
Muenke syndrome Pathogenic:1
PS3,PS2,PM2,PP3
Cervical cancer Pathogenic:1
This variant was classified as: Pathogenic.
Malignant tumor of urinary bladder Pathogenic:1
Thanatophoric dysplasia, type 2;C1868678:Thanatophoric dysplasia type 1 Pathogenic:1
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0346629:Colorectal cancer;C0410529:Hypochondroplasia;C1300257:Thanatophoric dysplasia, type 2;C1336708:Germ cell tumor of testis;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer;C5774286:Lacrimoauriculodentodigital syndrome 2 Pathogenic:1
Skeletal dysplasia with acanthosis nigricans Pathogenic:1
Achondroplasia;C0005684:Malignant tumor of urinary bladder;C0153594:Malignant tumor of testis;C0265269:Levy-Hollister syndrome;C0334082:Epidermal nevus;C0410529:Hypochondroplasia;C0699790:Carcinoma of colon;C1300257:Thanatophoric dysplasia, type 2;C1864436:Muenke syndrome;C1864852:Camptodactyly-tall stature-scoliosis-hearing loss syndrome;C1868678:Thanatophoric dysplasia type 1;C2674173:Severe achondroplasia-developmental delay-acanthosis nigricans syndrome;C2677099:Crouzon syndrome-acanthosis nigricans syndrome;C4048328:Cervical cancer Pathogenic:1
Multiple myeloma Pathogenic:1
Thanatophoric dysplasia, type 2 Pathogenic:1
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.
Hamartoma Pathogenic:1
Small for gestational age;C0345371:Lower limb undergrowth;C0349588:Short stature;C0410528:Skeletal dysplasia;C0426790:Narrow chest;C0426817:Short ribs;C0456070:Growth delay;C1837406:Upper limb undergrowth;C1849937:Disproportionate short-limb short stature;C1859460:Bowed humerus;C1859461:Femoral bowing;C1865186:Bell-shaped thorax;C2674171:Lethal short-limbed short stature Pathogenic:1
Connective tissue disorder Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at