ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1118A>G (p.Tyr373Cys) (rs121913485)

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Total submissions: 16
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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 RCV001000011 SCV000603706 pathogenic none provided 2020-02-14 criteria provided, single submitter clinical testing The p.Tyr373Cys variant is a frequently identified variant associated with thanatophoric dysplasia, accounting for an estimated 15- 30 % of molecularly confirmed TD cases (Rousseau 1996 and Gomes 2018). In all cases this variant occurs de novo variant (Rousseau 1996 and Carss 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 16342), and it is also absent from general population databases (1000 Genomes, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. 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, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255235 SCV000708008 pathogenic not provided 2018-03-02 criteria provided, single submitter clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000017751 SCV000891504 uncertain significance Thanatophoric dysplasia type 1 2017-12-30 criteria provided, single submitter curation
Invitae RCV000797516 SCV000937076 pathogenic Craniosynostosis syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 373 of the FGFR3 protein (p.Tyr373Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in several individuals affected with thanatophoric dysplasia (PMID: 8845844, 24476948, 28249712) and is the second most common cause of this condition (PMID: 25614871). ClinVar contains an entry for this variant (Variation ID: 16342). This variant has been reported to alter dimerization of the FGFR3 protein (PMID: 25606676), cause significant growth arrest compared to cells with wild-type FGFR3 (PMID: 19088846) and show defects in the growth-plate architecture in mouse models with this variant (PMID: 23200862, 24419316). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik 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 Karolinska University Hospital,Karolinska University Hospital RCV000255235 SCV001449880 pathogenic not provided 2017-01-25 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 pathologic Thanatophoric dysplasia type 1 2013-09-12 no assertion criteria provided curation Converted during submission to Pathogenic.
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 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

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