ClinVar Genomic variation as it relates to human health

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP2,PP3.

The FGFR2 c.758C>G; p.Pro253Arg variant (rs77543610) is reported in the literature in several individuals with craniosynostosis disorders including reports of the variant developing de novo (selected references: Ibarra-Arce 2015, Ibrahimi 2001, Slaney 1996, Wang 2021, Wilkie 1995). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 13273) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The amino acid at this position is moderately conserved but computational analyses predict that this variant is deleterious (REVEL: 0.724) In support of this prediction, this variant is predicted to increase ligand binding (Ibrahimi 2001) and a mouse model recapitulates aspects of disease (Martinez-Abadias 2013). Based on available information, this variant is classified as pathogenic. References: Ibarra-Arce A et al. Mutations in the FGFR2 gene in Mexican patients with Apert syndrome. Genet Mol Res. 2015 14(1):2341-2346. Ibrahimi OA et al. Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. Proc Natl Acad Sci U S A. 2001 98(13):7182-7187. Martinez-Abadias N et al. From shape to cells: mouse models reveal mechanisms altering palate development in Apert syndrome. Dis Model Mech. 2013 May;6(3):768-79. Slaney SF et al. Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Am J Hum Genet. 1996 58(5):923-932. Wang H et al. Diagnostic and clinical utility of next-generation sequencing in children born with multiple congenital anomalies in the China neonatal genomes project. Hum Mutat. 2021 Apr;42(4):434-444. Wilkie AO et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet. 1995 9(2):165-172.

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 253 of the FGFR2 protein (p.Pro253Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Apert syndrome (PMID: 7668257, 7719344, 8651276, 9677057, 17251833, 24656465, 25867380). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13273). 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 FGFR2 protein function. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 9700203, 15389579, 20489451). For these reasons, this variant has been classified as Pathogenic.

The missense variant p.P253R in FGFR2 (NM_000141.5) has been reported in multiple affected individuals and is reported in upto 30% of affected individuals (Nur BG et al, Ibarra-Arce et al, Wilkie AO et al). Functional studies reveal a damaging effect (Baroni T et al). The variant has been submitted to ClinVar as Pathogenic. The p.P253R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.P253R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 253 of FGFR2 is conserved in all mammalian species. The nucleotide c.758 in FGFR2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013273). A different missense change at the same codon (p.Pro253Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000829801). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

A heterozygous missense variation in exon 7 of the FGFR2 gene that results in the amino acid substitution of Arginine for Proline at codon 253 was detected. The variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions# of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species.

Published functional studies demonstrate a gain of function resulting in increased ligand binding and receptor activation of the mutant receptor compared to wild-type receptors (Anderson et al., 1998); Published animal studies demonstrate significant defects in palate morphogenesis in mouse models compared to wild-type littermates (Martinez-Abadias et al., 2013); 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; This variant is associated with the following publications: (PMID: 31837199, 23754559, 28523332, 29483804, 29868125, 15282208, 34667527, 23325524, 25350236, 24566675, 25867380, 11596961, 12477974, 24656465, 25297884, 23546041, 7719344, 23915865, 17537644, 24486773, 18242159, 8651276, 28717660, 28123344, 28650109, 28826843, 19077386, 17243131, 19940464, 16969861, 30355600, 30258940, 30692697, 32510873, 33502061, Pitirri2021[abstract], 33937142, 35591945, 34358384, 34094714, 10067911, 9973282, 25271085, 9700203, 23519026)

The FGFR2 c.758C>G variant is predicted to result in the amino acid substitution p.Pro253Arg. This variant has been well-documented to be pathogenic for Apert syndrome (see for example Wilkie et al. 1995. PubMed ID: 7719344; Carinci et al. 2002. PubMed ID: 12477974; Athanasiadis et al. 2008. PubMed ID: 19077386; Bourdeaut et al. 2013. PubMed ID: 23325524; Alghamdi et al. 2021. PubMed ID: 33937142). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar it has been classified as pathogenic or likely pathogenic by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/13273/). This variant is interpreted as pathogenic.