Submissions for variant NM_000141.5(FGFR2):c.758C>G (p.Pro253Arg)

dbSNP: rs77543610

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000014193	SCV000328369	pathogenic	Acrocephalosyndactyly type I	2016-09-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000489611	SCV000577419	pathogenic	not provided	2023-04-25	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532721	SCV000659619	pathogenic	FGFR2-related craniosynostosis	2025-02-02	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FGFR2 protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000762803	SCV000893153	pathogenic	Acrocephalosyndactyly type I; Beare-Stevenson cutis gyrata syndrome; Jackson-Weiss syndrome; Levy-Hollister syndrome; Pfeiffer syndrome; Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis; Crouzon syndrome; Saethre-Chotzen syndrome; Familial scaphocephaly syndrome, McGillivray type; Neoplasm of stomach; Bent bone dysplasia syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000489611	SCV001247452	pathogenic	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197223	SCV001367860	pathogenic	Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP2,PP3.
Department of Medical Genetics, Oslo University Hospital	RCV000014193	SCV001437546	pathogenic	Acrocephalosyndactyly type I		criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000489611	SCV002048578	pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000014193	SCV002073114	pathogenic	Acrocephalosyndactyly type I		criteria provided, single submitter	clinical testing	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.
3billion, Medical Genetics	RCV000014193	SCV002572939	pathogenic	Acrocephalosyndactyly type I	2022-09-01	criteria provided, single submitter	clinical testing	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.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000014193	SCV002600893	pathogenic	Acrocephalosyndactyly type I	2022-08-19	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000489611	SCV003833339	likely pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000014193	SCV005400426	pathogenic	Acrocephalosyndactyly type I	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FGFR2-related disorders (PMIDs: 29848297, 32879300, 27323706). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable expressivity has been reported for Crouzon syndrome (MIM#123500) whereby some relatives can have mild phenotypic manifestations and can seem unaffected (PMID:20301628). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Pro253Leu) has been reported in ClinVar twice as likely pathogenic. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported sixteen times in ClinVar as pathogenic and is a common recurring variant seen in 26-33% of all Apert syndrome cases (PMID:31145570). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000014193	SCV000034441	pathogenic	Acrocephalosyndactyly type I	2006-10-15	no assertion criteria provided	literature only
Baylor Genetics	RCV000014193	SCV000854607	pathogenic	Acrocephalosyndactyly type I	2018-11-18	no assertion criteria provided	clinical testing
GeneReviews	RCV000014193	SCV000929992	not provided	Acrocephalosyndactyly type I		no assertion provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000489611	SCV001955496	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000489611	SCV001964130	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000489611	SCV002035535	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532335	SCV004115949	pathogenic	FGFR2-related disorder	2023-12-27	no assertion criteria provided	clinical testing	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.