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

dbSNP: rs121913484

Total submissions: 8

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