Submissions for variant NM_000142.5(FGFR3):c.158G>C (p.Ser53Thr)

gnomAD frequency: 0.00014  dbSNP: rs201433984

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592095	SCV000707708	uncertain significance	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV000592095	SCV002507818	uncertain significance	not provided	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 53 of the FGFR3 protein (p.Ser53Thr). This variant is present in population databases (rs201433984, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FGFR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 501373). 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 not expected to disrupt FGFR3 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488721	SCV004240898	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: FGFR3 c.158G>C (p.Ser53Thr) results in a conservative amino acid change in Immunoglobulin subtype 2 domain (IPR003598) in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 246024 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.158G>C has been reported in the literature in one individual affected with Hepatoblastoma (Aguiar_2022), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Achondroplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35495172). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843532	SCV002103101	likely pathogenic	Hepatoblastoma		no assertion criteria provided	research