10-121520160-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_022970.4(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P253L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

FGFR2
NM_022970.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: 9.99

Publications

295 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Apert syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
Beare-Stevenson cutis gyrata syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp
Crouzon syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, PanelApp Australia, Genomics England PanelApp, G2P
Jackson-Weiss syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
LADD syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Pfeiffer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
bent bone dysplasia syndrome 1
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
familial scaphocephaly syndrome, McGillivray type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
Saethre-Chotzen syndrome
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
Antley-Bixler syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
LADD syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Pfeiffer syndrome type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Pfeiffer syndrome type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Pfeiffer syndrome type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FGFR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_022970.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-121520160-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 829801.

PP2

Missense variant in the FGFR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.402 (below the threshold of 3.09). Trascript score misZ: 4.3638 (above the threshold of 3.09). GenCC associations: The gene is linked to Pfeiffer syndrome type 3, Crouzon syndrome, Apert syndrome, Antley-Bixler syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, bent bone dysplasia syndrome 1, Pfeiffer syndrome, Saethre-Chotzen syndrome, LADD syndrome 1, familial scaphocephaly syndrome, McGillivray type, LADD syndrome, Pfeiffer syndrome type 1, Pfeiffer syndrome type 2, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 13273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_022970.4 link	c.758C>G	p.Pro253Arg	missense_variant	Exon 7 of 18	ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5 link	c.758C>G	p.Pro253Arg	missense_variant	Exon 7 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FGFR2	ENST00000457416.7 link	c.758C>G	p.Pro253Arg	missense_variant	Exon 7 of 18	1	NM_022970.4	ENSP00000410294.2
FGFR2	ENST00000358487.10 link	c.758C>G	p.Pro253Arg	missense_variant	Exon 7 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000369056.5 link	c.758C>G	p.Pro253Arg	missense_variant	Exon 6 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7 link	c.758C>G	p.Pro253Arg	missense_variant	Exon 7 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4 link	c.491C>G	p.Pro164Arg	missense_variant	Exon 6 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369059.5 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 5 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7 link	c.491C>G	p.Pro164Arg	missense_variant	Exon 6 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5 link	c.74C>G	p.Pro25Arg	missense_variant	Exon 6 of 17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5 link	n.413C>G		non_coding_transcript_exon_variant	Exon 5 of 17	1		ENSP00000474109.1
FGFR2	ENST00000369061.8 link	c.749-4841C>G		intron_variant	Intron 5 of 14	1		ENSP00000358057.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acrocephalosyndactyly type I

Pathogenic:8Other:1

Aug 19, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Nov 18, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 17, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Department of Medical Genetics, Oslo University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 01, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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 -

not provided

Pathogenic:7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 08, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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 the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. 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. PMID: 25867380. 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. PMID: 11390973. 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. PMID: 23519026. 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. PMID: 8651276. 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. PMID: 33502061. 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. PMID: 7719344. -

Apr 25, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FGFR2: PS2, PS4, PM2, PS3:Moderate -

FGFR2-related craniosynostosis

Pathogenic:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

FGFR2-related disorder

Pathogenic:1

Dec 27, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method: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. -

Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

(source)

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

LIST_S2

Benign

0.81

T;T;T;T;T;T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.7

.;.;L;.;.;L;.;L;.;L;.;L;L;.

PhyloP100

PrimateAI

Pathogenic

0.80

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

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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