Submissions for variant NM_000141.5(FGFR2):c.755C>T (p.Ser252Leu)

gnomAD frequency: 0.00001  dbSNP: rs79184941

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000664049	SCV000787470	benign	Crouzon syndrome	2018-04-16	criteria provided, single submitter	curation	This variant is interpreted as a Benign, for Crouzon syndrome, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:9002682). BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:9002682).
Mendelics	RCV000664049	SCV001138181	likely benign	Crouzon syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000664049	SCV001430659	likely benign	Crouzon syndrome	2020-06-30	criteria provided, single submitter	clinical testing
Invitae	RCV001313539	SCV001504038	uncertain significance	FGFR2-related craniosynostosis	2023-01-28	criteria provided, single submitter	clinical testing	This variant is also known as 934C>T. This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 9002682, 11711827, 27683237). This variant is present in population databases (rs79184941, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 252 of the FGFR2 protein (p.Ser252Leu). ClinVar contains an entry for this variant (Variation ID: 549484). 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. This variant disrupts the p.Ser252 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7719344, 8651276, 9462761, 11390973, 22664175, 23495007, 24489893, 25867380). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FGFR2 function (PMID: 9700203). 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 FGFR2 protein function.
GeneDx	RCV002298724	SCV002588317	uncertain significance	not provided	2022-10-14	criteria provided, single submitter	clinical testing	Reported in individuals with Crouzon syndrome, inherited from apparently unaffected parents (Oldridge et al., 1997; Ohishi et al., 2017); Reported in a family where affected members had severe syndactyly without craniosynostosis and harbored a second FGFR2 variant in cis with p.(S252L) (Wilkie et al., 2002).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15282208, 15840724, 9700203, 26003532, 17621648, 9300656, 27683237, 32908727, 31348830, 9002682, 12357470, 29037998, 20301628)
PreventionGenetics, part of Exact Sciences	RCV003403529	SCV004105740	uncertain significance	FGFR2-related condition	2022-10-04	criteria provided, single submitter	clinical testing	The FGFR2 c.755C>T variant is predicted to result in the amino acid substitution p.Ser252Leu. This variant has been reported in several individuals with Crouzon syndrome, but it has also been observed in clinically normal members with the families (Oldridge et al 1997. PubMed ID: 9002682; Sakai N et al 2001. PubMed ID: 11711827; Ohishi et al. 2016. PbuMed ID: 27683237). In one study, functional analysis of this variant revealed wild-type kinetic (Anderson J et al 1998. PubMed ID: 9700203). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-123279677-G-A). A different substitution affecting the same amino acid (p.Ser252Trp) has been reported in association with Apert syndrome (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV002298724	SCV004134775	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	FGFR2: BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987651	SCV004804229	uncertain significance	not specified	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: FGFR2 c.755C>T (p.Ser252Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. c.755C>T has been reported in the literature in two independent families affected with Crouzon syndrome and the variant was present in both affected individuals as well as clinically normal family members (examples: Oldridge_1997, Oshini_2017). Additionally, this variant was seen in cis with a second pathogenic variant in a mother and her daughter affected with syndactyly (Wilkie_2002). At least one publication reports experimental evidence that FGFR2 mutant Ser252Leu exhibited kinetic behavior identical to wild-type (Anderson_1998). These data suggest a benign role for this variant however, other variants affecting this residue have been classified pathogenic/likely pathogenic in ClinVar (CV IDs: 13272, 13279). ClinVar contains an entry for this variant (Variation ID: 549484). The following publications have been ascertained in the context of this evaluation (PMID: 9002682, 9700203, 15282208, 11711827, 27683237, 12357470). Based on the evidence outlined above, the variant was classified as uncertain significance.