c.1172T>G (p.Met391Arg) in FGFR2 is a missense variant in the transmembrane domain, identified as a de novo change in three unrelated individuals with Bent Bone Dysplasia-FGFR2 type, a perinatal lethal skeletal dysplasia.1 Functional studies directly testing FGFR2 p.Met391Arg demonstrated reduced plasma membrane localization and diminished responsiveness to extracellular FGF2/FGF18 (absent ERK1/2 phosphorylation) in patient-derived chondrocytes and BaF3 cells.2 Independent functional characterization confirmed enhanced nucleolar localization of the mutant receptor, with increased rDNA transcription, elevated osteoprogenitor proliferation, and decreased differentiation, providing a mechanistic basis for the BBDS phenotype.3 The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), and in silico predictors (REVEL 0.817, BayesDel 0.381) consistently support a deleterious effect.4 Criteria met: PS3 (strong), PM1 (moderate), PM2 (supporting), PM6 (supporting), PP3 (supporting). Using the ACMG/AMP 2015 combination rules, this yields a classification of PATHOGENIC (1 strong + 1 moderate + 3 supporting).5
FGFR2
Final classification
Likely Pathogenic
FGFR2 c.1172T>G · p.Met391Arg
FGFR2
c.1172T>G (p.Met391Arg) in FGFR2 is a missense variant in the transmembrane domain, identified as a de novo change in three unrelated individuals with Bent Bone Dysplasia-FGFR2 type, a perinatal lethal skeletal dysplasia.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 supporting, PM6 supporting, PP3 supporting; combination = 1 strong + 1 moderate + 3 supporting, which maps to Likely Pathogenic.
Classification rationale
PS3PM1PM2PM6PP3
Likely Pathogenic
FGFR2 c.1172T>G
PS3 + PM1 + PM2 + PM6 + PP3
→
Likely Pathogenic
4
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗revelbayesdel
5
generic_acmg_combination_rules
Gene diagram
· NM_000141.4 · variants mapped to exon structure
FGFR2
NM_000141.4
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 16 assessed
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
strong
Pathogenic
The exact variant FGFR2 p.Met391Arg (c.1172T>G) was directly tested in functional studies across two independent publications. Merrill et al. (2012) demonstrated reduced plasma membrane localization, diminished FGF responsiveness (no ERK1/2 phosphorylation upon FGF2/FGF18 stimulation), and nuclear retention in patient-derived chondrocytes and BaF3 cells. Neben et al. (2014) further showed enhanced nucleolar localization of the mutant receptor, increased rDNA transcription, elevated osteoprogenitor proliferation, and decreased differentiation. The functional effect is unequivocal and mechanistically linked to the BBDS disease phenotype.
PMID:22387015: Patient-derived primary chondrocytes and BaF3 cells — reduced plasma membrane FGFR2diminished FGF responsiveness (absent ERK1/2 phosphorylation)nuclear retention.
✓
PM1
moderate
Pathogenic
The variant is located in the transmembrane domain of FGFR2 (residue 391), a critical functional domain essential for receptor integration into the lipid bilayer and plasma membrane localization. Merrill et al. (2012) demonstrated that the p.Met391Arg substitution introduces a polar amino acid into the hydrophobic transmembrane helix, disrupting its secondary structure as predicted by TMHMM analysis. The transmembrane domain is a well-characterized functional domain required for FGFR2 signaling.
Located in FGFR2 transmembrane domain (residue 391).TMHMM analysis confirms disruption of the transmembrane helix by p.Met391Arg.Experimentally demonstrated loss of membrane integration and plasma membrane localization.
✓
PM2
supporting
Pathogenic
c.1172T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0). The variant meets the PM2 threshold of <0.1% population frequency.
Absent from gnomAD v2.1 (AF = 0).Absent from gnomAD v4.1 (AF = 0).Absent from gnomAD-Canada v1.0 (AF = 0).
✓
PM6
supporting
Pathogenic
c.1172T>G was identified as de novo in three unrelated individuals with Bent Bone Dysplasia-FGFR2 type. Parental DNA was tested and confirmed absent in two of the three cases. Maternity and paternity were not explicitly confirmed via identity testing, so PM6 (assumed de novo) is applied at supporting strength.
Three unrelated cases with de novo c.1172T>G.Parental DNA tested and variant absent in 2 of 3 cases.GeneDx submission (SCV000582486) also reports presumed de novo.
✓
PP3
supporting
Pathogenic
REVEL score of 0.817 strongly predicts a damaging effect. BayesDel score of 0.381 is above the typical 0.27 threshold. SpliceAI max delta score of 0.21 is borderline but consistent with a possible splice impact. Multiple in silico predictors support a deleterious effect on the protein.
REVEL score: 0.817 (damaging).BayesDel score: 0.381 (above 0.27 threshold).SpliceAI max delta: 0.21 (borderline
Assessed · not applied
Pathogenic
PS2
De novo status is not confirmed with both maternity and paternity testing.
PS4
No large-scale case-control study demonstrating statistically significant enrichment of c.1172T>G in affected individuals versus controls.
PP1
No segregation data available.
PP2
No HCI prior score or missense constraint data available for FGFR2.
PP4
No proband phenotype provided in the case materials.
PP5
ClinVar classification is Pathogenic (Variation ID 29855) with review status 'criteria provided, single submitter' (1 star).
Benign
BA1
Variant is absent from all gnomAD datasets (AF = 0%).
BS1
Variant is absent from all gnomAD datasets (AF = 0%).
BS2
No evidence of observation in healthy adults.
BS3
Functional studies demonstrate a damaging effect (see PS3).
BS4
No evidence of non-segregation with disease in affected families.
BP1
FGFR2 missense variants are a well-established cause of multiple autosomal dominant skeletal disorders (including BBDS, Apert, Crouzon, Pfeiffer, LADD syndromes).
BP2
No evidence of observation in trans with a pathogenic FGFR2 variant.
BP4
Multiple in silico tools predict a damaging effect (see PP3).
BP5
No evidence that the variant was found in a case with an alternate molecular basis for disease.
BP6
ClinVar does not have a benign or likely benign classification from a ≥3-star expert panel.
N/A · 7
PVS1 · PS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 29855)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.21). REVEL score = 0.817. BayesDel score = 0.380974.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 1 further PMID triaged but not cited — see Sources & References.
Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.
Searched
c.1172T>Gp.Met391ArgM391RMet391Arg
Found
Merrill et al. identified c.1172T>G (p.Met391Arg) as a de novo heterozygous missense mutation in three unrelated fetuses with Bent Bone Dysplasia-FGFR2 type, a perinatal lethal skeletal dysplasia with deficient calvarial mineralization, craniosynostosis, and bent long bones. Functional studies in patient chondrocytes and BaF3 cells showed reduced plasma membrane FGFR2, diminished FGF2/FGF18 responsiveness, and nuclear receptor retention.
Variant
✓ Names this variant — characterised directly
Applied to
→PM1 supports · met
→PM6 supports · met
→PS3 supports · met
Why
Variant-specific functional and de novo evidence confirmed; referenced in PS3 (strong), PM1 (moderate), and PM6 (supporting) assessments.
Three independent cases (R07-401, R08-041, and R96-252) shared the same de novo missense mutation, c.1172T>G
Location Results; Figure 3A-C; Figure 4 · Context Primary human femoral growth plate chondrocytes, BaF3 cells (murine pro-B cell line lacking endogenous FGFRs), immunofluorescence, immunoblot, biotin cell-surface labeling, qPCR · full text
Bent bone dysplasia syndrome reveals nucleolar activity for FGFR2 in ribosomal DNA transcription.
Searched
c.1172T>Gp.Met391ArgM391RMet391ArgFGFR2M391RFGFR2M391R
Found
Neben et al. demonstrated that the FGFR2 p.Met391Arg mutation, despite reducing canonical plasma membrane signaling, enhances nucleolar localization of FGFR2. The mutant receptor activates ribosomal DNA transcription via interactions with FGF2 and UBF1, leading to increased rRNA levels, osteoprogenitor proliferation, and decreased differentiation.
Variant
✓ Names this variant — characterised directly
Applied to
→PM1 supports · met
→PS3 supports · met
Why
Independent functional data confirmed enhanced nucleolar FGFR2 activity; referenced in PS3 (strong) and PM1 (moderate) assessments.
The dominant FGFR2 mutations in BBDS, p.Met391Arg or p.Tyr381Asp, are located in the transmembrane domain, selectively reduce plasma membrane levels of FGFR2 and consequently diminish receptor responsiveness to extracellular FGFs.
Location Introduction; Results (Figures 1-7); Discussion · Context MC3T3-E1 mouse calvarial preosteoblasts, HEK 293T cells, primary human BBDS growth plate cells, ChIP-qPCR, rDNA minigene reporter, subnuclear fractionation · full text
Sources & reference links
Triaged references · 1 PMID not cited in assessment