Submissions for variant NM_000142.5(FGFR3):c.1118A>G (p.Tyr373Cys)

dbSNP: rs121913485

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255235	SCV000322321	pathogenic	not provided	2020-04-24	criteria provided, single submitter	clinical testing	Published functional studies indicate that the Y373C variant causes increased activation of the receptor in the absence of the ligand (Ronchetti et al., 2001; Qi et al., 2014); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21273588, 19331127, 11851976, 9843049, 30692697, 8845844, 30712878, 25606676, 24419316, 24476948, 22045636, 11429702, 24657641, 19088846, 23200862, 17509076, 17320202, 14715624, 11526491, 26858415, 29593476, 28249712, 19789973, 9438390, 31299979)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255235	SCV000603706	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	The FGFR3 c.1118A>G; p.Tyr373Cys variant (rs121913485) is reported in the literature in multiple individuals affected with thanatophoric dwarfism (Brodie 1999, Rousseau 1996), and it was identified in a cohort of fetal skeletal dysplasia patients (Carass 2014). This variant is reported in ClinVar (Variation ID: 16342), and it is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Carass et al. found the p.Tyr373Cys variant to be de novo in a male fetus with features consistent with lethal skeletal dysplasia. Furthermore, a mouse model of the p.Tyr373Cys variant displays features similar to achondroplasia (Di Rocco 2014, Lorget 2012) and in vitro studies performed on the p.Tyr373Cys variant in human chondrocytes show decreased proliferation (Krejci 2008). The tyrosine at codon 373 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.800). Based on available information, this variant is considered to be pathogenic. References: Brodie SG et al. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. Am J Med Genet. 1999 Jun 11;84(5):476-80. PMID: 10360402. Carss et al. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum Mol Genet. 2014; 23(12):3269-3277. PMID: 24476948. Di Rocco et al. FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Hum Mol Genet. 2014; 23(11):2914-2925. PMID: 24419316. Krejci et al. Analysis of STAT1 Activation by Six FGFR3 Mutants Associated with Skeletal Dysplasia Undermines Dominant Role of STAT1 in FGFR3 Signaling in Cartilage. PLoS One. 2008;3(12):e3961. PMID: 19088846. Lorget F et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet. 2012 Dec 7;91(6):1108-14. PMID: 23200862. Rousseau et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet. 1996; 5(4):509-512. PMID: 8845844.
Eurofins Ntd Llc (ga)	RCV000255235	SCV000708008	pathogenic	not provided	2018-03-02	criteria provided, single submitter	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000017751	SCV000891504	uncertain significance	Thanatophoric dysplasia type 1	2017-12-30	criteria provided, single submitter	curation
Invitae	RCV000255235	SCV000937076	pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the FGFR3 protein (p.Tyr373Cys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR3 function (PMID: 19088846, 23200862, 24419316, 25606676). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt FGFR3 function. ClinVar contains an entry for this variant (Variation ID: 16342). This missense change has been observed in individual(s) with thanatophoric dysplasia (PMID: 8845844, 24476948, 25614871, 28249712). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).
CeGaT Center for Human Genetics Tuebingen	RCV000255235	SCV001247232	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255235	SCV001447317	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000255235	SCV001449880	pathogenic	not provided	2017-01-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255235	SCV002023072	pathogenic	not provided	2020-05-25	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000017751	SCV002053824	pathogenic	Thanatophoric dysplasia type 1		criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000017751	SCV002761903	pathogenic	Thanatophoric dysplasia type 1	2021-11-22	criteria provided, single submitter	clinical testing	The FGFR3 c.1118A>G variant is a single nucleotide change in exon 9/18 of the FGFR3 gene, which is predicted to change the amino acid tyrosine at position 373 in the protein to cysteine. This variant has been identified as a de novo variant in this patient (PS2). This variant is absent from population databases (PM2), but has been reported numerous times in the literature in association with Thanatophoric dwarfism and Achondroplasia (e.g. PMID: 8845844, 24476948, 28249712) (PS4). It is the second most common cause of this condition (PMID:25614871). The variant has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 16342) and is listed in HGMD as disease causing (CM960657). Computational predictions support a deleterious effect on the gene or gene product (PP3). Functional studies reproducing the equivalent variant in mouse models mirrored the clinical presentation seen in humans (Lorget et al 2012 PMID: 23200862) (PS3).
Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	RCV000017751	SCV003915612	pathogenic	Thanatophoric dysplasia type 1	2021-04-16	criteria provided, single submitter	clinical testing
OMIM	RCV000017751	SCV000038029	pathogenic	Thanatophoric dysplasia type 1	1998-11-16	no assertion criteria provided	literature only
GeneReviews	RCV000017751	SCV000086707	not provided	Thanatophoric dysplasia type 1		no assertion provided	literature only
Database of Curated Mutations (DoCM)	RCV000421104	SCV000504980	likely pathogenic	Myeloproliferative disorder	2014-12-26	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434824	SCV000504981	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442248	SCV000504982	likely pathogenic	Urinary bladder carcinoma	2016-03-10	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427428	SCV000504983	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419796	SCV000506428	likely pathogenic	Carcinoma	2016-05-13	no assertion criteria provided	literature only
Baylor Genetics	RCV000017751	SCV000854610	pathogenic	Thanatophoric dysplasia type 1	2018-11-18	no assertion criteria provided	clinical testing
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	RCV003155034	SCV003844094	pathogenic	See cases	2021-08-20	no assertion criteria provided	research