rs776587763

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000141.5(FGFR2):​c.833G>T​(p.Cys278Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C278Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FGFR2
NM_000141.5 missense

Scores

17
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.90
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a disulfide_bond (size 64) in uniprot entity FGFR2_HUMAN there are 35 pathogenic changes around while only 1 benign (97%) in NM_000141.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
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: 4.4365 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.992
PP5
Variant 10-121520085-C-A is Pathogenic according to our data. Variant chr10-121520085-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 265431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121520085-C-A is described in Lovd as [Pathogenic]. Variant chr10-121520085-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGFR2NM_000141.5 linkc.833G>T p.Cys278Phe missense_variant Exon 7 of 18 ENST00000358487.10 NP_000132.3 P21802-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGFR2ENST00000358487.10 linkc.833G>T p.Cys278Phe missense_variant Exon 7 of 18 1 NM_000141.5 ENSP00000351276.6 P21802-1
FGFR2ENST00000457416.7 linkc.833G>T p.Cys278Phe missense_variant Exon 7 of 18 1 ENSP00000410294.2 P21802-3
FGFR2ENST00000369056.5 linkc.833G>T p.Cys278Phe missense_variant Exon 6 of 17 1 ENSP00000358052.1 P21802-17
FGFR2ENST00000369058.7 linkc.833G>T p.Cys278Phe missense_variant Exon 7 of 17 1 ENSP00000358054.3 A0A5S6RJB7
FGFR2ENST00000613048.4 linkc.566G>T p.Cys189Phe missense_variant Exon 6 of 17 5 ENSP00000484154.1 D2CGD1
FGFR2ENST00000369059.5 linkc.488G>T p.Cys163Phe missense_variant Exon 5 of 16 5 ENSP00000358055.1 E7EVR7
FGFR2ENST00000360144.7 linkc.566G>T p.Cys189Phe missense_variant Exon 6 of 17 2 ENSP00000353262.3 P21802-22
FGFR2ENST00000478859.5 linkc.149G>T p.Cys50Phe missense_variant Exon 6 of 17 1 ENSP00000474011.1 S4R381
FGFR2ENST00000369061.8 linkc.749-4766G>T intron_variant Intron 5 of 14 1 ENSP00000358057.4 P21802-23
FGFR2ENST00000604236.5 linkn.488G>T non_coding_transcript_exon_variant Exon 5 of 17 1 ENSP00000474109.1 S4R3B2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251442
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Oct 27, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a gain of function effect (Li et al., 2013); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23754559, 12884424, 24127277, 23906837, 16844695, 23348274, 25361936, 7655462, 20004243, 10874645, 11596961, 27228464, 28849010, 21686735, 32005694, 31837199, 32410215, 33502061) -

Aug 10, 2020
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Cys278Phe variant is a recurrent pathogenic variant and is one of the most commonly detected variants in individuals with Crouzon syndrome (PMID: 7655462, 25361936, 24127277 and others). The same variant has been reported in individuals with Pfeiffer syndrome, multisuture craniosynostosis, and in an individual with Crouzon syndrome with a tracheal cartilaginous sleeve (PMID: 24127277, 10874645, 27228464). The FGFR2 p.Cys278Phe variant has been found to be a de novo change in some individuals, and has also been demonstrated to segregate with the phenotype in families with multiple affected members (PMID: 7655462). This variant has been observed in a single individual in the Genome Aggregation Database (1 of 251,442 alleles; v2.1.1). -

Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

FGFR2: PP1:Strong, PS2, PM1, PS4:Moderate, PP3 -

FGFR2-related craniosynostosis Pathogenic:2
-
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 278 of the FGFR2 protein (p.Cys278Phe). This variant is present in population databases (rs776587763, gnomAD 0.0009%). This missense change has been observed in individual(s) with Pfeiffer syndrome or multisuture craniosynostosis (PMID: 7655462, 10874645, 23348274, 24127277, 25361936). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265431). 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 expected to disrupt FGFR2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Crouzon syndrome Pathogenic:2
Nov 12, 2009
Department of Medical Genetics, Oslo University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 24, 2019
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 variant in exon 7 of the FGFR2 gene that results in the amino acid substitution of Phenylalanine for Cystine at codon 278 was detected. The observed variation lies in the immunoglobuline set domain of the FGFR2 protein and has previously been reported in patients affected with Crouzon syndrome and functional studies show the pathogenic affect of the observed variant (Li et al. Hum Mol Genet 2013). The variant has not been reported in the 1000 genomes database and has allele frequency of 0.001% in ExAC database. In silico predictions show possibly damaging by PolyPhen-2 and damaging by SIFT, LRT and MutationTaster. In summary, the said variant meets our criteria to be classified as uncertain significance based on the mode of inheritance, in silico prediction and allele frequency in population databases. -

FGFR2-related disorder Pathogenic:1
Aug 06, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The FGFR2 c.833G>T variant is predicted to result in the amino acid substitution p.Cys278Phe. This variant has been previously reported, as a recurrent de novo or inherited, in individuals with Crouzon syndrome or other FGFR2-related disorder(s) (see, for example, Oldridge et al. 1995. PubMed ID: 7655462; Steinberger et al. 1999. PubMed ID: 10874645; Chokdeemboon et al. 2013. PubMed ID: 23348274; Roscioli et al. 2013. PubMed ID: 24127277; Sagong et al. 2014. PubMed ID: 25361936; Dong et al. 2020. PubMed ID: 32005694; Li et al. 2020. PubMed ID: 32410215). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (one heterozygous allele). This variant is interpreted as pathogenic. -

Pfeiffer syndrome Pathogenic:1
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

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
.;.;D;.;.;.;D;.;D;.;.;.;.;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
.;.;H;.;.;H;.;H;.;H;.;H;H;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-9.4
D;.;D;.;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;.;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen
1.0
D;.;.;.;P;.;.;.;.;.;D;D;.;.
Vest4
0.97
MutPred
0.95
.;.;Gain of catalytic residue at C278 (P = 0.0355);.;.;Gain of catalytic residue at C278 (P = 0.0355);.;Gain of catalytic residue at C278 (P = 0.0355);Gain of catalytic residue at C278 (P = 0.0355);Gain of catalytic residue at C278 (P = 0.0355);.;Gain of catalytic residue at C278 (P = 0.0355);Gain of catalytic residue at C278 (P = 0.0355);.;
MVP
0.97
MPC
1.9
ClinPred
1.0
D
GERP RS
5.8
Varity_R
1.0
gMVP
1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776587763; hg19: chr10-123279599; API