Submissions for variant NM_000142.5(FGFR3):c.749C>T (p.Pro250Leu)

dbSNP: rs4647924

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002233499	SCV000762845	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	This variant disrupts the p.Pro250 amino acid residue in FGFR3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9042914, 10094188, 10861678, 15915095, 26740388). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR3 protein function. ClinVar contains an entry for this variant (Variation ID: 533893). This missense change has been observed in individual(s) with clinical features of FGFR3-related conditions (PMID: 12362036). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 250 of the FGFR3 protein (p.Pro250Leu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003403475	SCV004105777	uncertain significance	FGFR3-related condition	2022-10-08	criteria provided, single submitter	clinical testing	The FGFR3 c.749C>T variant is predicted to result in the amino acid substitution p.Pro250Leu. This variant was reported in an individual with craniosynostosis and found to be inherited from her very mildly affected mother (Schindler et al 2002. PubMed ID: 12362036). This variant is reported in 0.0041% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-1803571-C-T). A different missense variant affecting the same amino acid is a common cause of isolated craniosynostosis (see for example, Kruszka. 2016. PubMed ID: 26740388 ). Although we suspect that this variant may be pathogenic, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.