Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
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 and Genomics, |
RCV000413645 | SCV001449937 | pathogenic | not provided | 2018-06-13 | criteria provided, single submitter | clinical testing | |
Centogene AG - |
RCV000017770 | SCV002059333 | pathogenic | Thanatophoric dysplasia type 1 | 2019-07-06 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000413645 | SCV003525755 | pathogenic | not provided | 2022-05-03 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with thanatophoric dysplasia type 1 (PMID: 8845844, 9790257, 24863959, 25614871). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 370 of the FGFR3 protein (p.Gly370Cys). ClinVar contains an entry for this variant (Variation ID: 16359). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 12009017). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). |
Medical Genetics Center, |
RCV000017770 | SCV003915610 | pathogenic | Thanatophoric dysplasia type 1 | 2022-12-05 | 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 | |
Gene |
RCV000017770 | SCV000086705 | not provided | Thanatophoric dysplasia type 1 | no assertion provided | literature only | ||
Database of Curated Mutations |
RCV000443051 | SCV000504979 | likely pathogenic | Urinary bladder carcinoma | 2015-07-14 | no assertion criteria provided | literature only | |
Molecular Genetics Laboratory, |
RCV003493410 | SCV004244264 | pathogenic | Thanatophoric dysplasia | 2024-01-10 | no assertion criteria provided | clinical testing |