10-121517351-G-C

Position:

• chr10-121517351-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The ENST00000358487.10(FGFR2):​c.1052C>G​(p.Ser351Cys) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGFR2 ENST00000358487.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.93

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 17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000358487.10
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR2. . Gene score misZ 2.402 (greater than the threshold 3.09). Trascript score misZ 4.4365 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.966
• PP5: Variant 10-121517351-G-C is Pathogenic according to our data. Variant chr10-121517351-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121517351-G-C is described in Lovd as [Pathogenic]. Variant chr10-121517351-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1052C>G	p.Ser351Cys	missense_variant	8/18	ENST00000358487.10	NP_000132.3
FGFR2	NM_022970.4	c.1087+1331C>G		intron_variant		ENST00000457416.7	NP_075259.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1052C>G	p.Ser351Cys	missense_variant	8/18	1	NM_000141.5	ENSP00000351276	A2
FGFR2	ENST00000457416.7	c.1087+1331C>G		intron_variant		1	NM_022970.4	ENSP00000410294	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pfeiffer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Human Genetics Unit, University Of Colombo	Dec 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 30, 2015	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2023	Recurrent variant in the immunoglobulin-like domain 3, typically associated with a severe form of Pfeiffer syndrome (Lajeunie et al., 2006; Stevens et al., 2006); 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: 8946174, 23754559, 16955501, 18391498, 34909104, 34367232, 30976282, 9714439, 10406670, 24127277, 23348274, 12544231, 20818252, 9605588, 15996217, 12072807, 16760743, 10633130, 29436723, 29280877, 29230096, 16465081, 9693549, 30355600, 31301044, 16418739, 31222448, 30976276, 32333414, 32732226, 34580403) -
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	-	- -

Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 25, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 13286). This missense change has been observed in individual(s) with severe forms of Crouzon or Pfeiffer syndromes (PMID: 8946174, 10406670, 16418739, 23348274, 24656465). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 351 of the FGFR2 protein (p.Ser351Cys). -

FGFR2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2024

The FGFR2 c.1052C>G variant is predicted to result in the amino acid substitution p.Ser351Cys. This variant has been well documented to be pathogenic for Pfeiffer syndrome (Gripp et al. 1998. PubMed ID: 9714439; Chokdeemboon et al. 2013. PubMed ID: 23348274; Nur BG et al 2014. PubMed ID: 24656465). It was also found in patients with Antley-Bixler and Beare-Stevenson syndromes (Roscioli et al. 2013. PubMed ID: 24127277). Additionally, this variant was documented in the de novo state in a fetus with Apert syndrome (Table S2. Fu et al. 2022. PubMed ID: 36307859). This variant is interpreted as pathogenic by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/13286/). This variant has not been reported in gnomAD, indicating it is rare. Taken together, this variant is interpreted as pathogenic. -

Crouzon syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

-

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.72). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013286 / PMID: 8946174). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Pfeiffer syndrome type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;.;D;.;.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.5	.;.;M;.;.;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PROVEAN	Uncertain	-3.0	D;.;D;.;D;D;.;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;.;D;.;D;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;.
Polyphen		0.98	D;.;.;.;P;.;.;.
Vest4		0.85
MutPred		0.88		.;.;Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);.;.;
MVP		0.88
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121918502; hg19: chr10-123276865; COSMIC: COSV105205525; COSMIC: COSV105205525;