rs776587763

chr10-121520085-C-Achr10-121520085-C-Gchr10-121520085-C-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C278L) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 23 ACMG points.

• PS1: Transcript NM_000141.5 (FGFR2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 578389
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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 chr10-121520084-GC-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374810.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, FGFR2
• 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/exons	MANE	UniProt
FGFR2	NM_022970.4	c.833G>T	p.Cys278Phe	missense_variant	7/18	ENST00000457416.7
FGFR2	NM_000141.5	c.833G>T	p.Cys278Phe	missense_variant	7/18	ENST00000358487.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000457416.7	c.833G>T	p.Cys278Phe	missense_variant	7/18	1	NM_022970.4	P4
FGFR2	ENST00000358487.10	c.833G>T	p.Cys278Phe	missense_variant	7/18	1	NM_000141.5	A2

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

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

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FGFR2-related craniosynostosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	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). 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) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

Crouzon syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jun 24, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Nov 12, 2009	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Aug 10, 2020	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). -

Pfeiffer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 17, 2016

- -

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
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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
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

Other links and lift over

dbSNP: rs776587763; hg19: chr10-123279599;