Variant classification summary

NM_023110.3:c.2267G>A

FGFR1 · NP_075598.2:p.(Arg756His) · NM_023110.3

GRCh37: chr8:38271461 C>T · GRCh38: chr8:38413943 C>T

Gene: FGFR1 Transcript: NM_023110.3

Final call

VUS

PS3 moderate PM2 supporting PP3 supporting

Variant details

Gene

FGFR1

Transcript

NM_023110.3

Protein

NP_075598.2:p.(Arg756His)

gnomAD AF

1.9828360752238436e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_023110.3:c.2267G>A (p.Arg756His) in FGFR1 is a missense variant in exon 17, located within the intracellular tyrosine kinase domain.

2

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).

3

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).

4

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).

5

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.

6

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).

7

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Missense substitution (p.Arg756His); does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No evidence of a different nucleotide change at the same position leading to the same amino acid substitution (p.Arg756His) being classified as pathogenic.
PS2	N/A	No de novo report identified for this variant.
PS3	Met	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.	PMID:21247312 pvs1_gene_context
PS4	Not met	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.	PMID:21247312 PMID:33337535 gnomad_v2 gnomad_v4
PS5	N/A	No evidence of a different nucleotide change at the same amino acid position (p.Arg756) being classified as pathogenic. PS5 requires an alternate nucleotide substitution producing the same missense change with a prior pathogenic classification.
PM1	Not met	Variant is located at residue 756 within the FGFR1 tyrosine kinase domain, a well-characterized functional domain. However, the position does not lie in a statistically significant mutational hotspot (cancerhotspots.org: residue_significant=false) and no locus-specific PM1 domain specification from CSPEC/VCEP is available for FGFR1. Functional domain alone, without demonstrated enrichment of pathogenic variants, does not satisfy PM1 in the generic ACMG/AMP framework.	PMID:21247312
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	Automated candidate harvesting could not confirm classic same-residue PM5 semantics; no pathogenic missense comparator variants identified at amino acid position 756.	pm5_candidates
PM6	N/A	No de novo report identified for this variant.
PP1	Not met	Limited segregation data available: Provenzano et al. (2021, PMID:33337535) reports the variant was inherited from the father, who had equivocal signs and symptoms of Chiari 1 malformation (±). Single-family observation with ambiguous phenotype in the carrier parent does not provide informative cosegregation evidence.	PMID:33337535
PP2	N/A	PP2 requires a gene with a high missense Z-score indicating low rate of benign missense variation. Gene-level missense constraint data (Z-score) for FGFR1 was not provided in the case materials and cannot be assessed.
PP3	Met	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 bayesdel spliceai
PP4	N/A	No patient phenotype or family history information was provided in the case materials to assess whether the phenotype is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar classification for this variant is Uncertain significance (3 clinical laboratories) with one additional Likely benign submission. No expert panel (≥3★) review classifies this variant as pathogenic. The ClinVar consensus does not meet the PP5 requirement of a reputable source reporting the variant as pathogenic.	clinvar
BA1	Not met	gnomAD v2.1 allele frequency is 0.00200%, well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD v2.1 allele frequency is 0.00200%, well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations in gnomAD. The variant was observed in heterozygous state in a parent with equivocal C1M phenotype (±) in Provenzano et al. (2021, PMID:33337535), which is insufficient to confirm observation in a healthy adult. False attribution of benign status to a variant with demonstrated functional loss (PS3) based on ambiguous carrier phenotype data is inappropriate.	PMID:33337535 gnomad_v2 gnomad_v4
BS3	Not met	Functional studies in Caronia et al. (2011, PMID:21247312) demonstrated loss of function for FGFR1 R756H, which is inconsistent with a benign effect. Evidence of damaging functional impact contradicts BS3 application.	PMID:21247312
BS4	N/A	No segregation data from multiple affected family members available to assess lack of cosegregation.
BP1	Not met	FGFR1-related disorders are caused by both missense and truncating variants. BP1 is applicable only when primarily truncating variants are known to cause disease, which is not the case for FGFR1.	pvs1_gene_context
BP2	N/A	No data on observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	Variant is a substitution, not an in-frame indel in a repetitive region.
BP4	Not met	REVEL score of 0.571 predicts a deleterious effect (threshold >0.5). SpliceAI shows no splicing impact (max delta=0.00). Computational evidence does not support a benign interpretation; REVEL is inconsistent with the multiple-lines-of-benign-evidence requirement for BP4.	revel bayesdel spliceai
BP5	N/A	No data on an alternate molecular basis for disease in a case carrying this variant.
BP6	Not met	One clinical laboratory (Fulgent Genetics, SCV002776725) classified this variant as Likely benign, but this is a single-submitter classification without expert panel review. No ≥3★ ClinVar expert panel classifies this variant as benign. The single-submitter Likely benign assertion does not meet the BP6 requirement for a reputable source consensus.	clinvar
BP7	N/A	Variant is missense (p.Arg756His), not synonymous. BP7 applies only to synonymous variants with no predicted splice impact.
PM3	N/A	No trans-configuration data for recessive disorders available.
PM4	N/A	Variant is a substitution, not a non-null protein length change.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.