Submissions for variant NM_000142.5(FGFR3):c.1879G>A (p.Glu627Lys)

gnomAD frequency: 0.00007  dbSNP: rs200849753

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Paul Sabatier University EA-4555, Paul Sabatier University	RCV000207413	SCV000259141	likely benign	Anophthalmia-microphthalmia syndrome	2013-01-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000711636	SCV000842022	uncertain significance	not provided	2018-06-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000711636	SCV001154149	uncertain significance	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711636	SCV002507675	uncertain significance	not provided	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 627 of the FGFR3 protein (p.Glu627Lys). This variant is present in population databases (rs200849753, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. 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: 221944). 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. 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.
Ambry Genetics	RCV002517390	SCV003723481	uncertain significance	Inborn genetic diseases	2022-06-10	criteria provided, single submitter	clinical testing	Unlikely to be causative of FGFR3-skeletal disorders syndrome (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689678	SCV005184966	uncertain significance	not specified	2024-05-23	criteria provided, single submitter	clinical testing	Variant summary: FGFR3 c.1879G>A (p.Glu627Lys) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250138 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FGFR3 causing Achondroplasia, allowing no conclusion about variant significance. c.1879G>A has been reported in the literature in at-least three individuals affected with disorders/differences of sex development and ocular developmental anomalies, without strong evidence for causality (Zidoune_2022, Chassaing_2016). 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 publications have been ascertained in the context of this evaluation (PMID: 26893459, 36110220). ClinVar contains an entry for this variant (Variation ID: 221944). Based on the evidence outlined above, the variant was classified as uncertain significance.