ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1108G>T (p.Gly370Cys) (rs121913479)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413645 SCV000491209 pathogenic not provided 2018-09-25 criteria provided, single submitter clinical testing The G370C missense variant in the FGFR3 gene has been reported in association with thanatophoric dysplasia and observed de novo (Rousseau F, et al., 1996; Katsumata N, et al. 1998; Xue Y, et al. 2014). Functional studies show 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 R, et al., 2002; You M, et al. 2007). The G370C variant is not observed in large population cohorts (Lek et al., 2016). The G370C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Similar missense variants in nearby residues (S371C, Y373C, G375C) have been reported in the Human Gene Mutation Database in association with thanatophoric dysplasia (Stenson et al., 2014), supporting the functional importance of this region of the protein.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000052 SCV000885455 pathogenic none 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
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 Bladder carcinoma 2015-07-14 no assertion criteria provided literature only

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