Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
ARUP Laboratories, |
RCV000757295 | SCV000885456 | pathogenic | not specified | 2019-04-11 | criteria provided, single submitter | clinical testing | The FGFR3 c.1111A>T; p.Ser371Cys variant (rs121913484) is a known pathogenic variant causative for thanatophoric dysplasia type I (Tavormina 1995, Karczeski 2013). It is reported as pathogenic in ClinVar (Variation ID 16333) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. In vitro functional studies have indicated the p.Ser371Cys variant promotes ligand-independent FGFR3 correct spatial dimerization that results in constitutive ligand independent phophorylation of MAPK and c-fos transcription (Adar 2002). Based on available information, this variant is considered pathogenic. REFERENCES Adar et al. Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization. J Bone Miner Res. 2002; 17(5): 860-868. Karczenski, B and Cutting, GR: Thanatophoric Dysplasia. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2017. 2004 May 21 (updated 2013 Sep 12). Tavormina PL et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 1995; 9(3):321-328. |
Gene |
RCV001528646 | SCV002513626 | pathogenic | not provided | 2022-05-10 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate ligand-independent, constitutive dimerization and phosphorylation of the MAPK and c-fos pathways (Adar et al., 2002; You et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22045636, 7773297, 8845844, 25157968, 28249712, 10587515, 12009017, 11181569, 17845056) |
OMIM | RCV000017736 | SCV000038014 | pathogenic | Thanatophoric dysplasia type 1 | 1995-03-01 | no assertion criteria provided | literature only | |
Gene |
RCV000017736 | SCV000086706 | pathologic | Thanatophoric dysplasia type 1 | 2013-09-12 | no assertion criteria provided | curation | Converted during submission to Pathogenic. |
Database of Curated Mutations |
RCV000431173 | SCV000505530 | likely pathogenic | Urinary bladder carcinoma | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441695 | SCV000510406 | likely pathogenic | Carcinoma | 2016-05-13 | no assertion criteria provided | literature only | |
Diagnostic Laboratory, |
RCV001528646 | SCV001740735 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001528646 | SCV001969322 | pathogenic | not provided | no assertion criteria provided | clinical testing |