ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1108G>T (p.Gly370Cys)

dbSNP: rs121913479
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413645 SCV000491209 pathogenic not provided 2021-11-24 criteria provided, single submitter clinical testing Published functional studies demonstrate p.(G370C) results in spontaneous disulfide bond-mediated dimerization of the FGFR3 protein independent of ligand stimulation that subsequently leads to constitutive activation of the receptor (Adar et al., 2002; You et al., 2007); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8845844, 15772091, 10471491, 25157968, 9790257, 12009017, 16841094, 19752524, 25728633, 25614871, 27028100, 28249712, 28254233, 10696568, 11745189, 24863959, 20301540, 19381019, 17845056)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000413645 SCV000885455 pathogenic not provided 2020-04-13 criteria provided, single submitter clinical testing The FGFR3 c.1108G>T; p.Gly370Cys variant (rs121913479) has been described in several individuals with thanatophoric dysplasia (TD), type I (Rousseau 1996, Katsumata 1998, Xue 2014). It is reported as pathogenic in ClinVar (Variation ID: 16359) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. In vitro functional studies have indicated the p.Gly370Cys variant promotes ligand-independent FGFR3 correct spatial dimerization that results in constitutive ligand independent phosphorylation of MAPK and c-fos transcription (Adar 2002). Based on available formation, this variant is considered 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;17(5): 860-868. Katsumata N et al. G370C mutation in the FGFR3 gene in a Japanese patient with thanatophoric dysplasia. Endocrin J 1998; 45 Suppl:S171-S174. Rousseau F et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet 1996; 5(4):509-512. Xue Y et al. FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry. Mol Genet Genomic Med 2014; 2(6): 497-503.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000413645 SCV001449937 pathogenic not provided 2018-06-13 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000017770 SCV002059333 pathogenic Thanatophoric dysplasia type 1 2019-07-06 criteria provided, single submitter clinical testing
OMIM RCV000017770 SCV000038048 pathogenic Thanatophoric dysplasia type 1 2006-08-01 no assertion criteria provided literature only
OMIM RCV000029208 SCV000051854 pathogenic Epidermal nevus 2006-08-01 no assertion criteria provided literature only
GeneReviews RCV000017770 SCV000086705 pathologic Thanatophoric dysplasia type 1 2013-09-12 no assertion criteria provided curation Converted during submission to Pathogenic.
Database of Curated Mutations (DoCM) RCV000443051 SCV000504979 likely pathogenic Urinary bladder carcinoma 2015-07-14 no assertion criteria provided literature only

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