10-121520160-G-C

Position:

• chr10-121520160-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):​c.758C>G​(p.Pro253Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P253P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 9.99

Genes affected

FGFR2 (HGNC:3689): (fibroblast growth factor receptor 2) The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]

FGFR2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR2. . Gene score misZ 2.402 (greater than the threshold 3.09). Trascript score misZ 4.4365 (greater than threshold 3.09). GenCC has associacion of gene with Pfeiffer syndrome type 3, Antley-Bixler syndrome, Pfeiffer syndrome type 2, Saethre-Chotzen syndrome, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome type 1, LADD syndrome 1, Pfeiffer syndrome, bent bone dysplasia syndrome 1, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, familial scaphocephaly syndrome, McGillivray type, Apert syndrome, LADD syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 10-121520160-G-C is Pathogenic according to our data. Variant chr10-121520160-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121520160-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.758C>G	p.Pro253Arg	missense_variant	7/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.758C>G	p.Pro253Arg	missense_variant	7/18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.758C>G	p.Pro253Arg	missense_variant	7/18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.758C>G	p.Pro253Arg	missense_variant	6/17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.758C>G	p.Pro253Arg	missense_variant	7/17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.491C>G	p.Pro164Arg	missense_variant	6/17	5		ENSP00000484154.1
FGFR2	ENST00000369059.5	c.413C>G	p.Pro138Arg	missense_variant	5/16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.491C>G	p.Pro164Arg	missense_variant	6/17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.74C>G	p.Pro25Arg	missense_variant	6/17	1		ENSP00000474011.1
FGFR2	ENST00000369061.8	c.749-4841C>G		intron_variant		1		ENSP00000358057.4
FGFR2	ENST00000604236.5	n.413C>G		non_coding_transcript_exon_variant	5/17	1		ENSP00000474109.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acrocephalosyndactyly type I Pathogenic:8 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 2006	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Nov 18, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 19, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	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 -

not provided Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

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. -

FGFR2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2023

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. -

Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

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

Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0038356:Neoplasm of stomach;C0175699:Saethre-Chotzen syndrome;C0220658:Pfeiffer syndrome;C0265269:Levy-Hollister syndrome;C0795998:Jackson-Weiss syndrome;C1852406:Beare-Stevenson cutis gyrata syndrome;C1865070:Familial scaphocephaly syndrome, McGillivray type;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3281247:Bent bone dysplasia syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	.;.;D;.;.;.;T;.;T;.;.;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.7	.;.;L;.;.;L;.;L;.;L;.;L;L;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.8	D;.;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;.;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.21	B;.;.;.;B;.;.;.;.;.;B;B;.;.
Vest4		0.76
MutPred		0.87		.;.;Loss of glycosylation at P253 (P = 0.0348);.;.;Loss of glycosylation at P253 (P = 0.0348);.;Loss of glycosylation at P253 (P = 0.0348);Loss of glycosylation at P253 (P = 0.0348);Loss of glycosylation at P253 (P = 0.0348);.;Loss of glycosylation at P253 (P = 0.0348);Loss of glycosylation at P253 (P = 0.0348);.;
MVP		0.92
MPC		1.8
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs77543610; hg19: chr10-123279674; COSMIC: COSV60644274; COSMIC: COSV60644274;