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

dbSNP: rs121913479

Total submissions: 12

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 and Genomics, 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413645	SCV003525755	pathogenic	not provided	2024-11-18	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 16359). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt FGFR3 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 12009017). For these reasons, this variant has been classified as Pathogenic.
Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	RCV000017770	SCV003915610	pathogenic	Thanatophoric dysplasia type 1	2022-12-05	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989295	SCV004806058	pathogenic	Achondroplasia	2024-03-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025064	SCV005662096	pathogenic	Achondroplasia; Camptodactyly-tall stature-scoliosis-hearing loss syndrome; Cervical cancer; Crouzon syndrome-acanthosis nigricans syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Malignant tumor of urinary bladder; Hypochondroplasia; Epidermal nevus; Severe achondroplasia-developmental delay-acanthosis nigricans syndrome; Colorectal cancer; Germ cell tumor of testis; Lacrimoauriculodentodigital syndrome 2	2024-01-12	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	not provided	Thanatophoric dysplasia type 1		no assertion provided	literature only
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV003493410	SCV004244264	pathogenic	Thanatophoric dysplasia	2024-01-10	no assertion criteria provided	clinical testing