FGFR2

Chr 10AD

fibroblast growth factor receptor 2

Also known as: BBDS, BEK, BFR-1, CD332, CEK3, CFD1, ECT1, JWS

NCBI Gene: 2263 ENSG00000066468 UniProt: P21802

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]

Primary Disease Associations & Inheritance

?Scaphocephaly, maxillary retrusion, and impaired intellectual developmentMIM #609579

Antley-Bixler syndrome without genital anomalies or disordered steroidogenesisMIM #207410

Apert syndromeMIM #101200

Beare-Stevenson cutis gyrata syndromeMIM #123790

Bent bone dysplasia syndromeMIM #614592

Craniofacial-skeletal-dermatologic dysplasiaMIM #101600

Craniosynostosis, nonspecific

Crouzon syndromeMIM #123500

Gastric cancer, somaticMIM #613659

Jackson-Weiss syndromeMIM #123150

LADD syndrome 1MIM #149730

Pfeiffer syndromeMIM #101600

Saethre-Chotzen syndromeMIM #101400

Scaphocephaly and Axenfeld-Rieger anomaly

UniProtFamilial scaphocephaly syndrome

UniProtLacrimo-auriculo-dento-digital syndrome 1

478

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— FGFR2

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Gene-Disease Validity (ClinGen)

Apert syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

6 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

50 Pathogenic / Likely Pathogenic· 243 VUS of 478 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.27LOEUF

pLI 0.997

Z-score 5.29

OE 0.14 (0.07–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.40Z-score

OE missense 0.69 (0.63–0.75)

323 obs / 469.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.14 (0.07–0.27)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.69 (0.63–0.75)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11

0≤1.21.6

LoF obs/exp: 6 / 43.8Missense obs/exp: 323 / 469.5Syn Z: -1.17

ClinVar Variant Classifications

478 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30

Likely Pathogenic20

VUS243

Likely Benign142

Benign21

Conflicting22

Pathogenic

Likely Pathogenic

243

VUS

142

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	12	14	0	30
Likely Pathogenic	1	14	5	0	20
VUS	3	196	33	11	243
Likely Benign	0	6	57	79	142
Benign	0	0	21	0	21
Conflicting	—				22
Total	8	228	130	90	478

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

FGFR2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

FGFR2-related lacrimo-auriculo-dento-digital syndrome (LADD)

definitive

ADGain Of FunctionAltered Gene Product Structure, Uncertain

Dev. DisordersSkinSkeletal

G2P ↗

missense variantinframe deletioninframe insertion

FGFR2-related Beare-Stevenson cutis gyrata syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkinSkeletal

G2P ↗

FGFR2-related Jackson-Weiss syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkin

G2P ↗

FGFR2-related Antley-Bixler syndrome

strong

ADUndeterminedAltered Gene Product Structure

Dev. Disorders

G2P ↗

missense variantinframe deletioninframe insertion

FGFR2-related Crouzon syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkinSkeletal

G2P ↗

FGFR2-related Apert Syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkinSkeletal

G2P ↗

FGFR2-related Pfeiffer syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkinSkeletal

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

FIBROBLAST GROWTH FACTOR RECEPTOR 2; FGFR2

MIM #176943 · *

?Scaphocephaly, maxillary retrusion, and impaired intellectual development

MIM #609579