ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.1948A>G (p.Lys650Glu) (rs78311289)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255799 SCV000322322 pathogenic not provided 2017-01-18 criteria provided, single submitter clinical testing The K650E missense variant in the FGFR3 gene has been reported previously in association with thanatophoric dysplasia and observed as de novo events (Tavormina et al., 1995; Huang et al., 2013). Functional studies indicate K650E results in constitutive autophosphorylation and activation of the receptor (Webster et al. 1997; Otsuka et al. 2011). The K650E missense variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. 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 position that is conserved across species. Other pathogenic missense variants in this residue (K650N, K650M, K650Q, K650T) have been reported in the Human Gene Mutation Database in association with skeletal dysplasias (Stenson et al., 2014), further supporting the functional importance of this residue in the protein.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000017728 SCV001364299 pathogenic Thanatophoric dysplasia, type 2 2020-04-23 criteria provided, single submitter research ACMG codes: PS2, PS3, PS4, PM2, PP3, PP4, PP5
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000255799 SCV001449563 pathogenic not provided 2014-08-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286286 SCV001472828 pathogenic none provided 2020-04-09 criteria provided, single submitter clinical testing The FGFR3 c.1948A>G; p.Lys650Glu variant (rs78311289) is reported in the literature as a de novo variant in multiple individuals affected with thanatophoric dysplasia type II (Tavormina 1995, Tonni 2014, Xue 2014). This variant is reported in ClinVar (Variation ID: 16331), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The lysine at codon 650 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show a gain of function leading to constitutive activation (Huang 2013, Livens 2003). Additionally, other amino acid substitutions at this codon (Met, Asn, Gln, Thr) have been reported in individuals with skeletal dysplasias and are considered pathogenic (Bellus 2000). Based on available information, this variant is considered to be pathogenic. References: Bellus GA et al. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000 Dec;67(6):1411-21. Huang Z et al. Structural mimicry of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation. Structure 2013 21(10):1889-1896. Lievens PM and Liboi E. The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. J Biol Chem 2003 278:17344-17349. Tavormina PL et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet 1995 9(3):321-328. Tonni G et al. Dysmorphic choroid plexuses and hydrocephalus associated with increased nuchal translucency: early ultrasound markers of de novo thanatophoric dysplasia type II with cloverleaf skull (Kleeblattschaedel). Congenit Anom (Kyoto) 2014 4(4):228-232. 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.
OMIM RCV000017728 SCV000038006 pathogenic Thanatophoric dysplasia, type 2 2009-11-01 no assertion criteria provided literature only
OMIM RCV000017729 SCV000038007 pathogenic Multiple myeloma 2009-11-01 no assertion criteria provided literature only
OMIM RCV000017730 SCV000038008 pathogenic Spermatocytic seminoma 2009-11-01 no assertion criteria provided literature only
GeneReviews RCV000017728 SCV000086708 pathologic Thanatophoric dysplasia, type 2 2013-09-12 no assertion criteria provided curation Converted during submission to Pathogenic.
Database of Curated Mutations (DoCM) RCV000433411 SCV000510408 likely pathogenic Carcinoma 2016-05-13 no assertion criteria provided literature only
Baylor Genetics RCV000017728 SCV000854612 pathogenic Thanatophoric dysplasia, type 2 2018-11-18 no assertion criteria provided clinical testing

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