10-121517378-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000141.5(FGFR2):c.1025G>A(p.Cys342Tyr) 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. 11/18 in silico tools predict a damaging 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. C342F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 7.85

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 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr10-121517378-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 374819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, FGFR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 10-121517378-C-T is Pathogenic according to our data. Variant chr10-121517378-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517378-C-T is described in Lovd as [Pathogenic]. Variant chr10-121517378-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_000141.5	c.1025G>A	p.Cys342Tyr	missense_variant	8/18	ENST00000358487.10
FGFR2	NM_022970.4	c.1087+1304G>A		intron_variant		ENST00000457416.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000358487.10	c.1025G>A	p.Cys342Tyr	missense_variant	8/18	1	NM_000141.5	A2
FGFR2	ENST00000457416.7	c.1087+1304G>A		intron_variant		1	NM_022970.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Crouzon syndrome Pathogenic:5

Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 30, 2020	The p.Cys342Tyr variant in FGFR2 has been reported in the literature in >20 individuals with syndromic craniosynostosis (such as Crouzon or Pfeiffer syndromes) and segregated with disease in four affected individuals from one family (Reardon 2013 PMID: 7987400; Schwartz 1996 PMID: 8650126; Roscioli 2013 PMID: 24127277; Paumard-Hernández 2015 PMID: 25271085). This variant was also confirmed de novo in a boy with a clinical diagnosis of Crouzon syndrome through trio WGS analysis by the Broad Institute Rare Genomes Project. This variant has been reported in ClinVar as pathogenic by multiple labs (Variation ID 13263). It is absent from large population studies. In vitro functional studies support an impact on protein function (Krejci 2012 PMID: 22558232), and animal models in mice have shown that this variant in heterozygous mice causes features of syndromic craniosynostosis (Eswarakumar 2004 PMID: 15316116). Additionally, other missense variants in this codon (p.Cys342Arg, p.Cys342Trp, p.Cys342Ser, p.Cys342Phe, p.Cys342Gly) have been identified in individuals with Crouzon syndrome suggesting that this position is critical for protein function. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant craniosynostosis. ACMG/AMP Criteria applied: PS2, PS3, PS4, PM1, PM2, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Feb 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2021	Published functional studies demonstrate that this variant results in aberrant cell growth and blocks cellular differentiation (Mansukhani et al., 2000), while experimental mice models demonstrate that p.(C342Y) leads to significant defects in skull development (Holmes et al., 2018); Not observed in large population cohorts (Lek et al., 2016); 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: 25692891, 20133659, 8650126, 25271085, 7719345, 9677057, 23754559, 24127277, 7987400, 27228464, 8644708, 11781872, 22558232, 15316116, 8755573, 7607643, 28901406, 26362256, 10851026, 31837199, 30048539) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

FGFR2-related craniosynostosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 30, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 342 of the FGFR2 protein (p.Cys342Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with syndromic craniosynostosis, including Crouzon or Pfeiffer syndromes (PMID: 7987400, 8650126, 24127277, 25271085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13263). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 8755573, 15316116, 20133659, 22558232). This variant disrupts the p.Cys342 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24127277, 25271085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

Pfeiffer syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1995

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 31, 2019

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP3,PP4. -

Craniosynostosis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Sep 02, 2021

The c.1025G>A;p.(Cys342Tyr) variant has been published as a pathogenic variant in individuals affected with syndromic craniosynostosis, including Crouzon or Pfeiffer syndromes (PMID: 7987400, 24127277, 25271085; GeneOne, DASA) - PS4; ClinVar contains an entry for this variant (Variation ID: 13263); Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 22558232, 8755573, 20133659, 15316116) - PS3; This variant is not present in population databases (rs121918487 - gnomAD no frequency; ABraOM no frequency - abraom.ib.usp.br) - PM2; Pathogenic missense variants in this residue (ClinVar ID: 374820 - c.1025G>C;p.(Cys342Ser); ClinVar ID: 374819 - c.1025G>T;p.(Cys342Phe)) - PM5; It has also been shown to segregate with Crouzon syndrome in a family (PMID: 8650126) - PP1; Missense variant in FGFR2 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2; In silico analysis predicts this variant is probably damaging to the protein structure/function - PP3; In summary, the currently available evidence indicates that the variant is pathogenic. -

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	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PROVEAN	Pathogenic	-8.5	D;.;D;.;D;D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D;.;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;D;.;.;.
Vest4		0.99
MutPred		0.99		.;.;Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);.;.;
MVP		0.95
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121918487; hg19: chr10-123276892;