rs121918497

Positions:

• chr10-121520052-T-G

Variant summary

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

The NM_000141.5(FGFR2):​c.866A>C​(p.Gln289Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as 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: 6.27

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000141.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FGFR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 10-121520052-T-G is Pathogenic according to our data. Variant chr10-121520052-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 13276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121520052-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_022970.4	c.866A>C	p.Gln289Pro	missense_variant	7/18	ENST00000457416.7
FGFR2	NM_000141.5	c.866A>C	p.Gln289Pro	missense_variant	7/18	ENST00000358487.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000457416.7	c.866A>C	p.Gln289Pro	missense_variant	7/18	1	NM_022970.4	P4
FGFR2	ENST00000358487.10	c.866A>C	p.Gln289Pro	missense_variant	7/18	1	NM_000141.5	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pfeiffer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
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:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2023	Not observed in large population cohorts (gnomAD); Within the immunoglobulin-like domain 3, in which pathogenic variants are typically associated with craniosynostosis phenotypes (Kan et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9385368, 23754559, 19066959, 7655462, 11781872, 8644708, 30355600, 7581378, 10712195, 16526917, 22355256, 24656465, 11173845, 12884424, 16470531, 32369273, 16418739, 35591945) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 12, 2018	DNA sequence analysis of the FGFR2 gene demonstrated a sequence change, c.866A>C, in exon 7 that results in an amino acid change, p.Gln289Pro. This sequence change is absent from population databases (ExAc and GnomAD) and it has been reported in multiple patients with craniosynostosis syndromes including Crouzon syndrome (PMIDs: 7655462, 22355256, 11781872), Pfeiffer syndrome (PMID: 19066959), Jackson-Weiss syndrome (PMID: 7581378) and Saethre-Chotzen Syndrome (PMID: 16526917). The p.Gln289Pro change affects a moderately conserved amino acid residue located in a domain of the FGFR2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln289Pro substitution. The p.Gln289Pro amino acid change occurs in a region of the FGFR2 gene where other missense sequence changes have been described in patients with FGFR2-related disorders. These collective evidences indicate that this sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively. -

FGFR2-related craniosynostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 289 of the FGFR2 protein (p.Gln289Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with FGFR2-related craniosynostosis syndromes, including Crouzon syndrome, and type 1 Pfeiffer syndrome (PMID: 7655462, 16418739, 19066959). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13276). 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%. For these reasons, this variant has been classified as Pathogenic. -

Crouzon syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1996

- -

Jackson-Weiss syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	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	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.9	D;.;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;D;.;D;T;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.99	D;.;.;.;D;.;.;.;.;.;P;D;.;.
Vest4		0.88
MutPred		0.86		.;.;Gain of catalytic residue at W290 (P = 0.0489);.;.;Gain of catalytic residue at W290 (P = 0.0489);.;Gain of catalytic residue at W290 (P = 0.0489);Gain of catalytic residue at W290 (P = 0.0489);Gain of catalytic residue at W290 (P = 0.0489);.;Gain of catalytic residue at W290 (P = 0.0489);Gain of catalytic residue at W290 (P = 0.0489);.;
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		5.8
Varity_R		1.0
gMVP		0.99

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: rs121918497; hg19: chr10-123279566;