10-121496701-T-G

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.1694A>C(p.Glu565Ala) 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. 12/21 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. E565G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.00

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 binding_site (size 2) in uniprot entity FGFR2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr10-121496701-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374823.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, 0.992
• PP5: Variant 10-121496701-T-G is Pathogenic according to our data. Variant chr10-121496701-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121496701-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_022970.4	c.1697A>C	p.Glu566Ala	missense_variant	13/18	ENST00000457416.7
FGFR2	NM_000141.5	c.1694A>C	p.Glu565Ala	missense_variant	13/18	ENST00000358487.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000457416.7	c.1697A>C	p.Glu566Ala	missense_variant	13/18	1	NM_022970.4	P4
FGFR2	ENST00000358487.10	c.1694A>C	p.Glu565Ala	missense_variant	13/18	1	NM_000141.5	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pfeiffer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013294). A different missense change at the same codon (p.Glu565Gly) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000374823). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely 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	literature only	OMIM	Dec 15, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Jun 16, 2020	- -

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2021

ClinVar contains an entry for this variant (Variation ID: 13294). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 15523615, 18541976, 24127277). 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 glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 565 of the FGFR2 protein (p.Glu565Ala). -

FGFR2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The FGFR2 c.1694A>C variant is predicted to result in the amino acid substitution p.Glu565Ala. This variant has been reported in individuals with Pfeiffer syndrome (arisen de novo, Zankl et al. 2004. PubMed ID: 15523615; Freeman et al. 2008. PubMed ID: 18541976; Table S2, Wang et al. 2021. PubMed ID: 33502061) as well as an individual with Crouzon syndrome (Roscioli et al. 2013. PubMed ID: 24127277). In vitro functional studies demonstrate that expression of this variant results in a gain of function by constitutively activating the kinase activity of FGFR2 (Chen et al. 2007. PubMed ID: 17803937). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been reported by several laboratories as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13294/). Additionally, a different missense change impacting the same amino acid (p.Glu565Gly) has been reported to segregate with disease in a family with Pfeiffer syndrome (Kan et al. 2002. PubMed ID: 11781872), supporting the evidence that this amino acid may be important for FGFR2 function. Taken together, the p.Glu565Ala variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2023

Not observed at 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: 18541976, 17803937, 15523615, 31911531, 34250419, 33218975, 24127277, 33731768, 33502061) -

Craniosynostosis syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.9	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.010	D;D;.;D;.;D;D;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.99, 1.0, 0.96, 1.0, 1.0	.;D;.;D;.;D;.;.;.;.;.;.;D;D;.;.
Vest4		0.97
MutPred		0.97		.;.;.;Loss of ubiquitination at K569 (P = 0.0468);.;.;.;.;.;.;Loss of ubiquitination at K569 (P = 0.0468);.;.;.;.;.;
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121918506; hg19: chr10-123256215; COSMIC: COSV105905071;