ClinVar Miner

Submissions for variant NM_000142.5(FGFR3):c.2420G>T (p.Ter807Leu) (rs397515514)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478851 SCV000568541 pathogenic not provided 2017-03-13 criteria provided, single submitter clinical testing The c.2420 G>T pathogenic variant in the FGFR3 gene has been previously reported in association with thanatophoric dysplasia 1 (Wilcox et al., 1998; Xue et al., 2014). This amino acid substitution results in the replacement of a Stop codon with a Leucine codon at amino acid position 807 and subsequenty extends the protein by 101 amino acids, denoted p.X807LextX101. Functional studies show that an equivalent extension due to the Stop codon variant (p.X807RextX101) results in constitutive activation of the receptor (Gibbs et al., 2007; Bonaventure et al., 2007). The c.2420 G>T variant is not observed in large population cohorts (Lek et al., 2016). Other stop codon variants resulting in protein extension (X807G/S/C/W/R) have been reported in the Human Gene Mutation Database in association with thanatophoric dysplasia (Stenson et al., 2014).
Invitae RCV000537188 SCV000640376 pathogenic Craniosynostosis syndrome 2017-08-11 criteria provided, single submitter clinical testing This sequence change disrupts the translational stop signal of the FGFR3 mRNA. It is expected to replace the original stop signal with a leucine residue and extend the length of the FGFR3 protein by 101 additional amino acid residues (p.*807Leuext*101). This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with thanatophoric dysplasia type I (PMID: 10425034, 25728633). This variant is also known as X807L and *807Leuext*102 in the literature. ClinVar contains an entry for this variant (Variation ID: 65562). Several other stop codon variants (p.*807Glyext*101, p.*807Argext*101, p.*807Cysext*101) have also been described in individuals with thanatophoric dysplasia type I, which result in the same length of a cysteine-rich, highly hydrophobic elongation at the C-terminus of FGFR3 protein (PMID: 7647778, 25614871). In addition, one of these variants (p.*807Argext*101) has been reported to disrupt the protein function and determined to be pathogenic (PMID: 17509076). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000055764 SCV000086713 pathologic Thanatophoric dysplasia type 1 2013-09-12 no assertion criteria provided curation Converted during submission to Pathogenic.

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