Total submissions: 50
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Shanghai First Maternity and Infant Hospital, |
RCV000017731 | SCV000282235 | pathogenic | Thanatophoric dysplasia type 1 | 2016-06-22 | criteria provided, single submitter | clinical testing | 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 |
Genomic Diagnostic Laboratory, |
RCV000017731 | SCV000328407 | pathogenic | Thanatophoric dysplasia type 1 | 2016-10-20 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000327823 | SCV000329627 | pathogenic | not provided | 2019-12-05 | criteria provided, single submitter | clinical testing | 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) |
Eurofins Ntd Llc |
RCV000327823 | SCV000334262 | pathogenic | not provided | 2018-08-13 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
RCV000414822 | SCV000492884 | pathogenic | Skeletal dysplasia; Short stature; Growth delay; Short ribs; Narrow chest; Small for gestational age; Bell-shaped thorax; Femoral bowing; Bowed humerus; Disproportionate short-limb short stature; Lethal short-limbed short stature; Lower limb undergrowth; Upper limb undergrowth | 2015-05-08 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000327823 | SCV000603712 | pathogenic | not provided | 2021-07-16 | criteria provided, single submitter | clinical testing | 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. |
Baylor Genetics | RCV000017731 | SCV000854614 | pathogenic | Thanatophoric dysplasia type 1 | 2022-03-30 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000763118 | SCV000893663 | pathogenic | Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Malignant tumor of urinary bladder; Hypochondroplasia; Epidermal nevus; Severe achondroplasia-developmental delay-acanthosis nigricans syndrome; Malignant tumor of testis; Carcinoma of colon | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
RCV001196297 | SCV001366881 | pathogenic | Cervical cancer | 2016-01-01 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. |
Invitae | RCV000327823 | SCV001389479 | pathogenic | not provided | 2023-12-11 | criteria provided, single submitter | clinical testing | 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. |
Institute Of Human Genetics Munich, |
RCV000017731 | SCV001430109 | pathogenic | Thanatophoric dysplasia type 1 | 2016-12-08 | criteria provided, single submitter | clinical testing | |
Clinical Genetics and Genomics, |
RCV000327823 | SCV001450204 | pathogenic | not provided | 2017-05-10 | criteria provided, single submitter | clinical testing | |
Equipe Genetique des Anomalies du Developpement, |
RCV001526641 | SCV001737072 | pathogenic | Hamartoma | criteria provided, single submitter | clinical testing | ||
Blueprint Genetics | RCV000327823 | SCV001832516 | pathogenic | not provided | 2020-03-13 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000327823 | SCV001962549 | pathogenic | not provided | 2021-08-01 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000327823 | SCV002023065 | pathogenic | not provided | 2024-01-11 | criteria provided, single submitter | clinical testing | |
Kasturba Medical College, |
RCV001804739 | SCV002053885 | pathogenic | Achondroplasia | criteria provided, single submitter | clinical testing | ||
DASA | RCV001849270 | SCV002107095 | pathogenic | FGFR3-related chondrodysplasia | 2022-03-05 | criteria provided, single submitter | clinical testing | 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. |
Daryl Scott Lab, |
RCV002243648 | SCV002515325 | pathogenic | FGFR3-related disorder | 2022-02-01 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV001804739 | SCV002516366 | pathogenic | Achondroplasia | 2022-05-04 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV002276552 | SCV002566636 | pathogenic | Connective tissue disorder | 2022-07-05 | criteria provided, single submitter | clinical testing | |
Daryl Scott Lab, |
RCV000017731 | SCV002567938 | pathogenic | Thanatophoric dysplasia type 1 | 2022-08-22 | criteria provided, single submitter | clinical testing | |
Genomic Medicine Lab, |
RCV000017731 | SCV002576369 | pathogenic | Thanatophoric dysplasia type 1 | criteria provided, single submitter | clinical testing | ||
Equipe Genetique des Anomalies du Developpement, |
RCV000017731 | SCV003920966 | pathogenic | Thanatophoric dysplasia type 1 | 2022-07-18 | criteria provided, single submitter | clinical testing | |
Institute for Clinical Genetics, |
RCV000327823 | SCV004025948 | pathogenic | not provided | 2022-01-10 | criteria provided, single submitter | clinical testing | |
Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV003388567 | SCV004100377 | pathogenic | Thanatophoric dysplasia, type 2 | criteria provided, single submitter | clinical testing | 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. | |
Prevention |
RCV003398532 | SCV004105863 | pathogenic | FGFR3-related condition | 2023-04-06 | criteria provided, single submitter | clinical testing | The FGFR3 c.742C>T variant is predicted to result in the amino acid substitution p.Arg248Cys. This variant has repeatedly been reported to be causative for autosomal dominant thanatophoric dysplasia (Tavormina et al. 1995. PubMed ID: 7773297; Camera et al. 2001. PubMed ID: 11754059; Castori et al. 2013. PubMed ID: 24038754; Table S3b, Wojcik et al. 2019. PubMed ID: 31395954; Table S1, Maddirevula et al. 2018. PubMed ID: 29620724). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. |
Division of Human Genetics, |
RCV000017731 | SCV004123085 | pathogenic | Thanatophoric dysplasia type 1 | 2023-07-01 | criteria provided, single submitter | research | |
Clinical Genomics Laboratory, |
RCV000017734 | SCV004176920 | pathogenic | Epidermal nevus | 2023-09-22 | criteria provided, single submitter | clinical testing | 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. |
Johns Hopkins Genomics, |
RCV000017731 | SCV004239071 | pathogenic | Thanatophoric dysplasia type 1 | 2023-09-21 | criteria provided, single submitter | clinical testing | 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001804739 | SCV004803862 | pathogenic | Achondroplasia | 2024-01-19 | criteria provided, single submitter | clinical testing | 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. |
Center for Genomic Medicine, |
RCV001804739 | SCV004804902 | pathogenic | Achondroplasia | 2024-03-17 | criteria provided, single submitter | research | |
OMIM | RCV000017731 | SCV000038009 | pathogenic | Thanatophoric dysplasia type 1 | 2008-09-01 | no assertion criteria provided | literature only | |
OMIM | RCV000017732 | SCV000038010 | pathogenic | Multiple myeloma | 2008-09-01 | no assertion criteria provided | literature only | |
OMIM | RCV000017733 | SCV000038011 | pathogenic | Skeletal dysplasia with acanthosis nigricans | 2008-09-01 | no assertion criteria provided | literature only | |
OMIM | RCV000017734 | SCV000038012 | pathogenic | Epidermal nevus | 2008-09-01 | no assertion criteria provided | literature only | |
OMIM | RCV000017735 | SCV000038013 | pathogenic | Seborrheic keratosis | 2008-09-01 | no assertion criteria provided | literature only | |
Gene |
RCV000017731 | SCV000086717 | not provided | Thanatophoric dysplasia type 1 | no assertion provided | literature only | ||
Database of Curated Mutations |
RCV000420041 | SCV000505529 | likely pathogenic | Lung adenocarcinoma | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000017732 | SCV000506416 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425802 | SCV000506417 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432622 | SCV000506418 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443913 | SCV000506419 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425165 | SCV000506420 | likely pathogenic | Carcinoma | 2016-05-13 | no assertion criteria provided | literature only | |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000327823 | SCV001955168 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000327823 | SCV001974802 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Institute of Medical Genetics and Genomics, |
RCV000017731 | SCV002072477 | pathogenic | Thanatophoric dysplasia type 1 | 2022-01-30 | no assertion criteria provided | clinical testing | 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. |
Institute Of Reproduction And Development, |
RCV003155030 | SCV003844074 | pathogenic | See cases | 2021-06-30 | no assertion criteria provided | research | |
Clinical Laboratory Sciences Program |
RCV000017731 | SCV003927941 | pathogenic | Thanatophoric dysplasia type 1 | 2023-04-01 | no assertion criteria provided | clinical testing | |
Laboratory of Urology, |
RCV003332082 | SCV004040569 | pathogenic | Malignant tumor of urinary bladder | no assertion criteria provided | research |