ClinVar Miner

Submissions for variant NM_000142.4(FGFR3):c.746C>G (p.Ser249Cys) (rs121913483)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000017742 SCV000854615 pathogenic Thanatophoric dysplasia type 1 2018-11-18 no assertion criteria provided clinical testing
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000017744 SCV000584006 pathogenic Bladder cancer, somatic 2017-07-24 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000431989 SCV000504978 likely pathogenic Bladder carcinoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435437 SCV000506421 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417690 SCV000506422 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424421 SCV000506423 likely pathogenic Carcinoma 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438171 SCV000506424 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420501 SCV000506425 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Fulgent Genetics,Fulgent Genetics RCV000763119 SCV000893664 pathogenic Achondroplasia; Camptodactyly, tall stature, and hearing loss syndrome; Carcinoma of cervix; Crouzon syndrome with acanthosis nigricans; Levy-Hollister syndrome; Muenke syndrome; Thanatophoric dysplasia type 1; Thanatophoric dysplasia, type 2; Bladder cancer, somatic; Hypochondroplasia; Epidermal nevus; Severe achondroplasia with developmental delay and acanthosis nigricans; Malignant tumor of testis; Carcinoma of colon 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000297175 SCV000329833 pathogenic not provided 2017-11-24 criteria provided, single submitter clinical testing The S249C missense variant in the FGFR3 gene has been reported in association with thanatophoric dysplasia I (TDI) and is one of five common, recurrent pathogenic variants responsible for this severe skeletal dysplasia (Rousseau et al., 1996; Tavormina et al., 1995; Del Piccolo et al. 2015). Functional studies indicate that S249C results in stable dimerization of the mutant protein and constitutive phosphorylation of the receptor (Tomlinson et al., 2007; Del Piccolo et al. 2015). It 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 conserved position within the linker region between Ig-like II and III where multiple disease-associated variants occur in the FGFR family of genes. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Another missense substitution to a cysteine at a nearby residue (R248C) also has been reported in association with TDI according to the Human Gene Mutation Database (Stenson et al., 2014). Finally, the S249C missense variant is not observed in large population cohorts (Lek et al., 2016). In summary, S249C is a common pathogenic variant and its presence is consistent with a diagnosis of thanatophoric dysplasia.
GeneReviews RCV000017742 SCV000086718 pathologic Thanatophoric dysplasia type 1 2013-09-12 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000800158 SCV000939858 pathogenic Craniosynostosis 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 249 of the FGFR3 protein (p.Ser249Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs121913483, ExAC 0.002%). This variant has been observed in several individuals affected with thanatophoric dysplasia (PMID: 8589699, 11038465, 11879084). ClinVar contains an entry for this variant (Variation ID: 16339). Experimental studies have shown that this missense change results in stable FGFR3 dimerization and constitutive phosphorylation of the receptor at higher levels than wild type protein (PMID: 17384684, 19749790, 25606676). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017742 SCV000038020 pathogenic Thanatophoric dysplasia type 1 2005-05-01 no assertion criteria provided literature only
OMIM RCV000017743 SCV000038021 pathogenic Carcinoma of cervix 2005-05-01 no assertion criteria provided literature only
OMIM RCV000017744 SCV000038022 pathogenic Bladder cancer, somatic 2005-05-01 no assertion criteria provided literature only
OMIM RCV000017745 SCV000038023 pathogenic Keratosis, seborrheic 2005-05-01 no assertion criteria provided literature only

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