Submissions for variant NM_000142.5(FGFR3):c.1663G>T (p.Val555Leu)

dbSNP: rs1474187970

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Goettingen	RCV002245545	SCV002515864	likely pathogenic	Hypochondroplasia	2022-05-20	criteria provided, single submitter	clinical testing	Comparison with the gnomAD browser did not provide any evidence that this sequence change is a norm variant that can also be detected in non-affected individuals. The mutation is currently not listed in ClinVar or in the HGMD database; the mutation is located in a protein domain of FGFR3 and affects a highly conserved amino acid; the mutation is independently classified as deleterious by four prediction programs; a probable pathogenic mutation has already been described at the above amino acid position in affected individuals with thanatophoric dysplasia (c.1663 G>A, p.(Val555Met) HGMD: CM133496, ClinVar: Variation ID: 988310, dbSNP: rs1474187970 (Marquis-Nicholson R. et al (2013) Sultan Qaboos Univ Med J. 13(1): 80-7) [PM5]; the following ACMG criteria were used for classification: PS1, PM1, PM2, PM5, PP2, PP3.
GeneDx	RCV002274252	SCV002559617	uncertain significance	not provided	2022-02-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV002274252	SCV002996266	uncertain significance	not provided	2023-03-12	criteria provided, single submitter	clinical testing	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FGFR3 protein function. ClinVar contains an entry for this variant (Variation ID: 1684537). This variant has not been reported in the literature in individuals affected with FGFR3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 555 of the FGFR3 protein (p.Val555Leu).