About FGFR2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FGFR2 c.1172T>G, p.(Met391Arg)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Strong
PS3 · strong
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.
PM1Moderate
PM1 · moderate
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.
PM2Supporting
PM2 · supporting
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.
PM6Supporting
PM6 · supporting
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.
PP3Supporting
PP3 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.210 maximum delta
Recorded SpliceAI maximum delta score: 0.210. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 5 met · 17 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
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).
No criteria match.
Met · 5
PS3 StrongThe 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. Details ▾Hide ▴
Evidence considered
- PMID:22387015: Patient-derived primary chondrocytes and BaF3 cells — reduced plasma membrane FGFR2
- diminished FGF responsiveness (absent ERK1/2 phosphorylation)
- nuclear retention.
- PMID:24908667: MC3T3-E1 preosteoblasts and HEK293T cells — enhanced nucleolar FGFR2
- increased rDNA transcription (45S pre-rRNA)
- elevated proliferation
- decreased osteoblast differentiation.
Sources
PM1 ModerateThe 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. Details ▾Hide ▴
Evidence considered
- 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.
Sources
PM2 Supportingc.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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0).
- Absent from gnomAD v4.1 (AF = 0).
- Absent from gnomAD-Canada v1.0 (AF = 0).
Sources
PM6 Supportingc.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. Details ▾Hide ▴
Evidence considered
- 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.
Still missing
- Paternity/maternity not explicitly confirmed via identity testing.
Sources
PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.817 (damaging).
- BayesDel score: 0.381 (above 0.27 threshold).
- SpliceAI max delta: 0.21 (borderline
- possible splice impact).
Sources
Not met · 17 · evaluated, threshold not reached
PS2 De novo status is not confirmed with both maternity and paternity testing. The variant was absent from available parental DNA in 2 of 3 cases but explicit identity testing was not reported. This evidence is captured under PM6 at supporting strength. Details ▾Hide ▴
Evidence considered
- Three unrelated cases with c.1172T>G absent from available parental DNA in 2 cases
- paternity/maternity identity testing not explicitly performed.
Still missing
- Lack of paternity/maternity confirmation via identity testing.
Sources
PS4 No large-scale case-control study demonstrating statistically significant enrichment of c.1172T>G in affected individuals versus controls. Only 4 affected individuals (3 with this variant) reported in a single publication. Details ▾Hide ▴
Evidence considered
- Four affected individuals across four unrelated families
- three with c.1172T>G. No case-control data available.
Still missing
- No case-control prevalence data available.
Sources
PP1 No segregation data available. The disorder is perinatal lethal, and all reported cases are sporadic. No multigenerational families identified for cosegregation analysis. Details ▾Hide ▴
Evidence considered
- No segregation data in the literature
- all reported cases are sporadic.
Still missing
- No multigenerational families for segregation analysis.
PP2 No HCI prior score or missense constraint data available for FGFR2. FGFR2 is known to have a mixture of gain-of-function and loss-of-function missense pathogenic variants, making a generic PP2 application inappropriate without gene-specific constraint metrics. Details ▾Hide ▴
Evidence considered
- HCI prior not available for FGFR2. FGFR2 has both activating and inactivating missense pathogenic variants
- generic PP2 not appropriate.
Still missing
- No gene-specific missense constraint metric available.
PP4 No proband phenotype provided in the case materials. Cannot assess whether the patient's specific clinical presentation is highly specific for FGFR2-related Bent Bone Dysplasia. Details ▾Hide ▴
Evidence considered
- No proband phenotype available for specificity assessment.
Still missing
- Patient phenotype not provided.
PP5 ClinVar classification is Pathogenic (Variation ID 29855) with review status 'criteria provided, single submitter' (1 star). PP5 requires ≥3-star expert panel review. The available ClinVar submissions (OMIM: no assertion criteria; GeneDx: single submitter) do not meet the 3-star expert panel threshold. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 29855: Pathogenic
- 1 star (criteria provided
- single submitter).
- No expert panel review available.
Still missing
- Lack of expert panel review in ClinVar.
Sources
BA1 Variant is absent from all gnomAD datasets (AF = 0%). Does not meet the BA1 threshold of >1% population frequency. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD
- AF = 0% (<1% threshold).
Sources
BS1 Variant is absent from all gnomAD datasets (AF = 0%). Does not meet the BS1 threshold of >0.3% population frequency. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD
- AF = 0% (<0.3% threshold).
Sources
BS2 No evidence of observation in healthy adults. The associated disorder (Bent Bone Dysplasia) is perinatal lethal; healthy adult carriers would not be expected. Details ▾Hide ▴
Evidence considered
- Variant associated with perinatal lethal disorder
- healthy adult observation not expected.
BS3 Functional studies demonstrate a damaging effect (see PS3). The variant is not benign; it causes reduced canonical FGFR2 signaling and enhanced nucleolar activity, both contributing to BBDS pathogenesis. Details ▾Hide ▴
Evidence considered
- PMID:22387015: Functional studies show damaging effect — reduced membrane FGFR2
- absent FGF responsiveness.
- PMID:24908667: Functional studies show damaging effect — increased rDNA transcription
- altered differentiation.
Sources
BS4 No evidence of non-segregation with disease in affected families. All reported cases are sporadic; no multigenerational families available. Details ▾Hide ▴
Evidence considered
- No segregation data in unaffected individuals.
BP1 FGFR2 missense variants are a well-established cause of multiple autosomal dominant skeletal disorders (including BBDS, Apert, Crouzon, Pfeiffer, LADD syndromes). BP1 applies only when the disease mechanism is exclusively truncating, which is not the case for FGFR2. Details ▾Hide ▴
Evidence considered
- FGFR2 disorders are primarily caused by missense variants
- BP1 not applicable.
BP2 No evidence of observation in trans with a pathogenic FGFR2 variant. FGFR2-associated disorders are autosomal dominant with perinatal lethality in severe forms; observation in trans is not expected. Details ▾Hide ▴
Evidence considered
- No in trans observations
- autosomal dominant disorder.
BP4 Multiple in silico tools predict a damaging effect (see PP3). REVEL 0.817, BayesDel 0.381, and SpliceAI 0.21 do not support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL 0.817: damaging prediction.
- BayesDel 0.381: above benign threshold.
- SpliceAI 0.21: borderline but not benign.
Sources
BP5 No evidence that the variant was found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis identified.
BP6 ClinVar does not have a benign or likely benign classification from a ≥3-star expert panel. The only ClinVar classification is Pathogenic (1 star). BP6 threshold is not met. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Pathogenic
- not benign
- no 3-star expert panel review.
Sources
PS5 No alternative pathogenic variant at the same amino acid residue (Met391) with a different substitution identified. The other BBDS variant (p.Tyr381Asp) is at a different residue. Details ▾Hide ▴
Evidence considered
- No alternative pathogenic change at residue 391 identified.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/Ac.1172T>G is a missense substitution (p.Met391Arg) in exon 9 of FGFR2. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The variant-level assessment confirms apply_generic_pvs1_framework is false. Details ▾Hide ▴
Evidence considered
- Missense variant in exon 9
- variant_bucket='other'
- not eligible for generic PVS1 framework.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo evidence of a different nucleotide change at the same codon producing the same amino acid substitution (p.Met391Arg). No alternate nucleotide variant at c.1172 was identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No same-amino-acid alternate nucleotide change identified.
PM3 N/AFGFR2-associated disorders are autosomal dominant, not recessive. PM3 (in trans with a pathogenic variant) does not apply. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis is a missense substitution, not a protein-length altering variant (in-frame deletion/insertion, stop-loss, or initiation codon change). Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variants (alternate amino acid changes at Met391) identified in ClinVar. The PM5 candidate search returned zero same-residue candidates. Cannot apply PM5 without a pathogenic comparator at the same residue. Details ▾Hide ▴
Evidence considered
- No pathogenic variants at the same residue (Met391) identified in ClinVar.
Sources
pm5_candidates
BP3 N/AThis is a missense variant, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/Ac.1172T>G is a missense variant (p.Met391Arg), not a synonymous variant. BP7 criteria for synonymous variants with no predicted splice impact do not apply. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- FGFR2
- Transcript
- NM_000141.4
- Coding (HGVS c.)
- NM_000141.4:c.1172T>G
- Protein (HGVS p.)
- NP_000132.3:p.(Met391Arg)
- GRCh38
- chr10:121515232 A>C
- GRCh37
- chr10:123274746 A>C
- ClinVar
- 29855
Gene diagram
Every interpreted variant in FGFR2, mapped onto the exon structure of NM_000141.4. Select a row to find it on the plot.
FGFR2NM_000141.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FGFR2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.817
- BayesDel
- 0.381
How the predictions were used
PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.817 (damaging).
- BayesDel score: 0.381 (above 0.27 threshold).
- SpliceAI max delta: 0.21 (borderline
- possible splice impact).
Sources
BP4 Multiple in silico tools predict a damaging effect (see PP3). REVEL 0.817, BayesDel 0.381, and SpliceAI 0.21 do not support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL 0.817: damaging prediction.
- BayesDel 0.381: above benign threshold.
- SpliceAI 0.21: borderline but not benign.
Sources
BP7 N/Ac.1172T>G is a missense variant (p.Met391Arg), not a synonymous variant. BP7 criteria for synonymous variants with no predicted splice impact do not apply. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.21). REVEL score = 0.817. BayesDel score = 0.380974.
3 paper records listed. 2 cited in the classification.
Cited in the classification
-
PMID 22387015 ↗Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.Merrill AE et al. · 2012 Mar 9Merrill 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.→ PS3 → PM1 → PM6 Names this variant
Source detail
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
-
PMID 24908667 ↗Bent bone dysplasia syndrome reveals nucleolar activity for FGFR2 in ribosomal DNA transcription.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.→ PS3 → PM1 Names this variant
Source detail
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
Other recorded publications
-
PMID 20301628 ↗FGFR Craniosynostosis Syndromes Overview.Adam MP et al. · 1993GeneReviews overview of FGFR craniosynostosis syndromes (Apert, Crouzon, Jackson-Weiss, Pfeiffer, Beare-Stevenson). Does not discuss Bent Bone Dysplasia-FGFR2 type or the specific c.1172T>G variant, which was discovered in 2012 after the 1993 initial posting.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.210
Open source ↗
ClinVar
1 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/29855/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-123274746-A-C?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-121515232-A-C?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-121515232-A-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000141.4%3Ac.1172…
- OncoKB ↗www.oncokb.org/gene/FGFR2/M391R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FGFR2+c.1172T%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.