NM_023110.3:c.2267G>A (p.Arg756His) in FGFR1 is a missense variant in exon 17, located within the intracellular tyrosine kinase domain. This variant is present at extremely low frequency in gnomAD v2.1 (AF=0.00200%, 5/249,890 alleles) and v4.1 (AF=0.00198%, 32/1,613,850 alleles), with no homozygotes observed (PM2_Supporting).1 Functional studies by Caronia et al. (2011) directly tested FGFR1 R756H and demonstrated loss of function: the mutant receptor showed significantly decreased FGF-induced MAPK reporter activity (OCFRE luciferase assay, P<0.001) while maintaining normal expression and cell-surface localization (PS3_Moderate).2 Multiple in silico tools provide mixed predictions; REVEL score of 0.571 supports a deleterious effect, while BayesDel (0.254) is equivocal and SpliceAI predicts no splicing impact (max delta=0.00) (PP3_Supporting).3 The variant has been reported in ClinVar as Uncertain significance by three clinical laboratories and as Likely benign by one laboratory (Variation ID: 1416171); no expert panel classification is available.4 This variant has been observed in two published cases: one individual with functional hypothalamic amenorrhea (Caronia 2011) and one individual with Chiari 1 malformation and trigonocephaly in whom the variant was inherited from a parent with equivocal phenotype (Provenzano 2021).5 Overall, combining 1 moderate pathogenic criterion (PS3) and 2 supporting pathogenic criteria (PM2, PP3) yields a classification of Likely Pathogenic per generic ACMG/AMP 2015 combination rules (1 moderate + ≥2 supporting → Likely Pathogenic).6
FGFR1
Final classification
VUS
FGFR1 c.2267G>A · p.Arg756His
FGFR1
NM_023110.3:c.2267G>A (p.Arg756His) in FGFR1 is a missense variant in exon 17, located within the intracellular tyrosine kinase domain.
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 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 2 supporting, which maps to VUS.
Classification rationale
PS3PM2PP3
VUS
FGFR1 c.2267G>A
PS3 + PM2 + PP3
→
VUS
3
revelbayesdelspliceai ↗
6
generic_acmg_combination_rules
Gene diagram
· NM_023110.3 · variants mapped to exon structure
FGFR1
NM_023110.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 11 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
moderate
Pathogenic
Functional studies in Caronia et al. (2011, PMID:21247312) directly tested FGFR1 R756H and demonstrated loss of function: the mutant receptor showed significantly decreased FGF-induced MAPK reporter activity (OCFRE luciferase assay, P<0.001), while total and cell-surface expression were comparable to wild-type. A single well-established in vitro functional study on the exact variant supports moderate-strength PS3 per PS3 calibration rules for a reporter-based assay.
Luciferase reporter assay (OCFRE) in L6 myoblasts and HEK293 cells showed FGFR1 R756H results in significant loss of MAPK signaling (P<0.001) compared to wild-type.Total and cell-surface expression of R756H mutant were comparable to wild-typeindicating the defect is in signaling rather than expression or trafficking.
✓
PM2
supporting
Pathogenic
Variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.00200% (5/249,890 alleles, 0 homozygotes), gnomAD v4.1 AF=0.00198% (32/1,613,850 alleles, 0 homozygotes), grpmax FAF=7.04e-06 (v2.1). Frequency is well below the 0.1% PM2 threshold. Absent from gnomAD-Canada v1.0.
gnomAD v2.1: 5/249890 alleles (AF=0.00200%)0 homozygotes
✓
PP3
supporting
Pathogenic
REVEL score of 0.571 predicts a deleterious effect (threshold >0.5). BayesDel score of 0.254 is equivocal. SpliceAI delta score of 0.00 indicates no predicted splicing impact. While computational evidence is mixed, REVEL supports a deleterious prediction at supporting strength.
REVEL: 0.571 (deleterious prediction>0.5 threshold)BayesDel: 0.254 (equivocal/borderline)
Assessed · not applied
Pathogenic
PS4
The variant has been observed in two published cases — one individual with hypothalamic amenorrhea (Caronia 2011, PMID:21247312) and one with Chiari 1 malformation and trigonocephaly (Provenzano 2021, PMID:33337535) — but no case-control study or statistically significant enrichment in affected individuals compared to population controls has been demonstrated.
PM1
Variant is located at residue 756 within the FGFR1 tyrosine kinase domain, a well-characterized functional domain.
PP1
Limited segregation data available: Provenzano et al.
PP5
ClinVar classification for this variant is Uncertain significance (3 clinical laboratories) with one additional Likely benign submission.
Benign
BA1
gnomAD v2.1 allele frequency is 0.00200%, well below the 1% BA1 threshold.
BS1
gnomAD v2.1 allele frequency is 0.00200%, well below the 0.3% BS1 threshold.
BS2
No homozygous observations in gnomAD.
BS3
Functional studies in Caronia et al.
BP1
FGFR1-related disorders are caused by both missense and truncating variants.
BP4
REVEL score of 0.571 predicts a deleterious effect (threshold >0.5).
BP6
One clinical laboratory (Fulgent Genetics, SCV002776725) classified this variant as Likely benign, but this is a single-submitter classification without expert panel review.
N/A · 14
PVS1 · PS1 · PS2 · PM3 · PM4 · PM5 · PM6 · PP2 · PP4 · BS4 · BP2 · BP3 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.98284e-05; MAF= 0.00198%, 32/1613850 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164366; MAF= 0.01644%, 1/6084 alleles, homozygotes = 0); grpmax FAF= 1.107e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.00088e-05; MAF= 0.00200%, 5/249890 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.27204e-05; MAF= 0.00327%, 1/30562 alleles, homozygotes = 0); grpmax FAF= 7.04e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.002%
· 32 / 1,613,850
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
Middle Eastern 1 / 6,084 |
0.016% |
Remaining individuals 6 / 62,480 |
0.0096% |
Admixed American 2 / 59,976 |
0.0033% |
African/African American 2 / 74,902 |
0.0027% |
European (non-Finnish) 20 / 1,179,956 |
0.0017% |
South Asian 1 / 91,060 |
0.0011% |
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.002%
· 5 / 249,890
0 hom · FAF 0.0007%
0 hom · FAF 0.0007%
South Asian 1 / 30,562 |
0.0033% |
Admixed American 1 / 34,486 |
0.0029% |
European (non-Finnish) 3 / 113,228 |
0.0026% |
+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 1416171)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.571. BayesDel score = 0.254117.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FGFR1, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types including lung and breas
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
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.
A genetic basis for functional hypothalamic amenorrhea.
Searched
c.2267G>Ap.Arg756HisR756HFGFR1
Found
FGFR1 R756H was identified in a patient with functional hypothalamic amenorrhea. Functional characterization in L6 myoblasts and HEK293 cells using an OCFRE luciferase reporter assay demonstrated significant loss of FGF-induced MAPK signaling (P<0.001) compared to wild-type FGFR1, with normal total and cell-surface receptor expression.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3 supports · met
Why
Exact variant functionally characterized with demonstrated loss of function; referenced in PS3 assessment at moderate strength.
The FGFR1 G260E and R756H mutants showed expression levels similar to those of wild-type FGFR1, both overall (Fig. 2F and 2G) and on the cell surface (Fig. 2I and 2J). However, results of a transcriptional assay show that the G260E and R756H mutants result in loss of function, as demonstrated by a decrease in FGF-induced MAPK reporter activity (reflected by OCFRE activity) (P<0.001) (Fig. 2L and 2M).
Location Results, paragraph 2; Figure 2F-2M; Table 2 · Context OCFRE luciferase reporter assay measuring MAPK signaling, performed in L6 myoblasts and HEK293 cells; total and cell-surface expression quantified by Western blot and antibody-binding assays in COS-7 cells. · full text
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
33337535 ↗
Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes.
CLINVAR