NM_000141.4:c.1172T>G

FGFR2 · NP_000132.3:p.(Met391Arg) · NM_000141.4

GRCh37: chr10:123274746 A>C · GRCh38: chr10:121515232 A>C

Gene: FGFR2 Transcript: NM_000141.4

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 supporting PM6 supporting PP3 supporting

Variant details

Gene

FGFR2

Transcript

NM_000141.4

Protein

NP_000132.3:p.(Met391Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	c.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.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No 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.
PS2	Not met	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.	PMID:22387015
PS3	Met	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 PMID:24908667
PS4	Not met	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.	PMID:22387015
PS5	Not met	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.
PM1	Met	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.	PMID:22387015 PMID:24908667
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Met	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.	PMID:22387015 clinvar
PP1	Not met	No segregation data available. The disorder is perinatal lethal, and all reported cases are sporadic. No multigenerational families identified for cosegregation analysis.
PP2	Not met	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.
PP3	Met	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 bayesdel spliceai
PP4	Not met	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.
PP5	Not met	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.	clinvar
BA1	Not met	Variant is absent from all gnomAD datasets (AF = 0%). Does not meet the BA1 threshold of >1% population frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from all gnomAD datasets (AF = 0%). Does not meet the BS1 threshold of >0.3% population frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence of observation in healthy adults. The associated disorder (Bent Bone Dysplasia) is perinatal lethal; healthy adult carriers would not be expected.
BS3	Not met	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.	PMID:22387015 PMID:24908667
BS4	Not met	No evidence of non-segregation with disease in affected families. All reported cases are sporadic; no multigenerational families available.
BP1	Not met	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.
BP2	Not met	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.
BP3	N/A	This is a missense variant, not an in-frame deletion/insertion in a repetitive region.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not met	No evidence that the variant was found in a case with an alternate molecular basis for disease.
BP6	Not met	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.	clinvar
BP7	N/A	c.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.
PM3	N/A	FGFR2-associated disorders are autosomal dominant, not recessive. PM3 (in trans with a pathogenic variant) does not apply.
PM4	N/A	This is a missense substitution, not a protein-length altering variant (in-frame deletion/insertion, stop-loss, or initiation codon change).

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