Total submissions: 24
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Peace Maternity and Child Health 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 | 2018-10-04 | criteria provided, single submitter | clinical testing | The R248C missense variant in the FGFR3 gene has been reported many times in association with thanatophoric dysplasia I (TDI) and is one of five common, recurrent pathogenic variants responsible for this severe skeletal dysplasia (Rousseau et al., 1996; Tavormina et al., 1995; Del Piccolo et al., 2015). Together with K373C, R248C accounts for 60% to 80% of all cases of TDI. Furthermore, functional studies indicate R248C results in structural perturbation of the FGFR3 dimer (Del Piccolo et al., 2015). It is a non-conservative amino acid substitution of a conserved arginine with a cysteine residue in the fibroblast growth factor receptor 3, which has been shown to lead to receptor overactivation and structural perturbation of FGFR3 dimers in vitro (Del Piccolo et al., 2015). Another missense substitution to a cysteine at a nearby residue (S249C) also has been reported in association with TDI according to the Human Gene Mutation Database (Stenson et al., 2014). Finally, R248C is not observed in large population cohorts (Lek et al., 2016), indicating it is not a common benign variant in these populations. |
EGL Genetic Diagnostics, |
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, |
RCV000999989 | SCV000603712 | pathogenic | none provided | 2020-06-01 | criteria provided, single submitter | clinical testing | The FGFR3 c.742C>T; p.Arg248Cys variant (rs121913482) is 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). 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). 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. |
Fulgent Genetics, |
RCV000763118 | SCV000893663 | pathogenic | Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Carcinoma of cervix; Crouzon syndrome with acanthosis nigricans; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Urinary bladder cancer; Hypochondroplasia; Epidermal nevus; Severe achondroplasia with developmental delay and acanthosis nigricans; Malignant tumor of testis; Carcinoma of colon | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
RCV001196297 | SCV001366881 | pathogenic | Carcinoma of cervix | 2016-01-01 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. |
Invitae | RCV001217632 | SCV001389479 | pathogenic | Craniosynostosis syndrome | 2019-06-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with cysteine at codon 248 of the FGFR3 protein (p.Arg248Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant is one of the most common causes of thanatophoric dysplasia and has been observed in several affected individuals (PMID: 10696568, 7773297, 11241532), including at least one case which was observed to be de novo (PMID: 7773297). ClinVar contains an entry for this variant (Variation ID: 16332). This variant has been reported to affect FGFR3 protein function (PMID: 1908846, 25606676). For these reasons, this variant has been classified as Pathogenic. |
Institute of Human Genetics, |
RCV000017731 | SCV001430109 | pathogenic | Thanatophoric dysplasia type 1 | 2016-12-08 | criteria provided, single submitter | clinical testing | |
Clinical Genetics Karolinska University Hospital, |
RCV000327823 | SCV001450204 | pathogenic | not provided | 2017-05-10 | criteria provided, single submitter | clinical testing | |
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 | pathologic | Thanatophoric dysplasia type 1 | 2013-09-12 | no assertion criteria provided | curation | Converted during submission to Pathogenic. |
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 | |
Baylor Genetics | RCV000017731 | SCV000854614 | pathogenic | Thanatophoric dysplasia type 1 | 2018-11-18 | no assertion criteria provided | clinical testing |