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
Consequence
NM_000141.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FGFR2 | ENST00000358487.10 | c.833G>T | p.Cys278Phe | missense_variant | Exon 7 of 18 | 1 | NM_000141.5 | ENSP00000351276.6 | ||
FGFR2 | ENST00000457416.7 | c.833G>T | p.Cys278Phe | missense_variant | Exon 7 of 18 | 1 | ENSP00000410294.2 | |||
FGFR2 | ENST00000369056.5 | c.833G>T | p.Cys278Phe | missense_variant | Exon 6 of 17 | 1 | ENSP00000358052.1 | |||
FGFR2 | ENST00000369058.7 | c.833G>T | p.Cys278Phe | missense_variant | Exon 7 of 17 | 1 | ENSP00000358054.3 | |||
FGFR2 | ENST00000613048.4 | c.566G>T | p.Cys189Phe | missense_variant | Exon 6 of 17 | 5 | ENSP00000484154.1 | |||
FGFR2 | ENST00000369059.5 | c.488G>T | p.Cys163Phe | missense_variant | Exon 5 of 16 | 5 | ENSP00000358055.1 | |||
FGFR2 | ENST00000360144.7 | c.566G>T | p.Cys189Phe | missense_variant | Exon 6 of 17 | 2 | ENSP00000353262.3 | |||
FGFR2 | ENST00000478859.5 | c.149G>T | p.Cys50Phe | missense_variant | Exon 6 of 17 | 1 | ENSP00000474011.1 | |||
FGFR2 | ENST00000369061.8 | c.749-4766G>T | intron_variant | Intron 5 of 14 | 1 | ENSP00000358057.4 | ||||
FGFR2 | ENST00000604236.5 | n.488G>T | non_coding_transcript_exon_variant | Exon 5 of 17 | 1 | ENSP00000474109.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251442Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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) -
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). -
FGFR2: PP1:Strong, PS2, PM1, PS4:Moderate, PP3 -
FGFR2-related craniosynostosis Pathogenic:2
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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
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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
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at