ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1111A>T (p.Ser371Cys)

dbSNP: rs121913484
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,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.
GeneDx 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
GeneReviews RCV000017736 SCV000086706 pathologic Thanatophoric dysplasia type 1 2013-09-12 no assertion criteria provided curation Converted during submission to Pathogenic.
Database of Curated Mutations (DoCM) RCV000431173 SCV000505530 likely pathogenic Urinary bladder carcinoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441695 SCV000510406 likely pathogenic Carcinoma 2016-05-13 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528646 SCV001740735 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001528646 SCV001969322 pathogenic not provided no assertion criteria provided clinical testing

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