About FGFR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FGFR1 c.2267G>A, p.(Arg756His)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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
confident-looking classification can still be wrong.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Moderate
PS3 · moderate
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.
PM2Supporting
PM2 · supporting
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.
PP3Supporting
PP3 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
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
32 / 1,613,850 alleles
gnomAD v4.1: 32 / 1,613,850 alleles. Recorded AF 1.98284e-05. Recorded homozygote count 0.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
4 reported laboratory submissions
3 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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
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: 3 met · 11 not met · 0 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
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).
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).
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.
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).
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).
No criteria match.
Met · 3
PS3 ModerateFunctional 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. Details ▾Hide ▴
Evidence considered
- 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-type
- indicating the defect is in signaling rather than expression or trafficking.
Still missing
- Single study with a reporter-based assay
- additional orthogonal functional validation would strengthen evidence.
Sources
PMID:21247312 ↗pvs1_gene_context
PM2 SupportingVariant 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 5/249
- 890 alleles (AF=0.00200%)
- 0 homozygotes
- gnomAD v4.1: 32/1
- 613
- 850 alleles (AF=0.00198%)
- grpmax FAF v2.1: 7.04e-06
- v4.1: 1.107e-05
- Absent from gnomAD-Canada v1.0
Sources
PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.571 (deleterious prediction
- >0.5 threshold)
- BayesDel: 0.254 (equivocal/borderline)
- SpliceAI max delta: 0.00 (no splice impact predicted)
Still missing
- BayesDel score is below typical damaging thresholds
- mixed in silico evidence.
Sources
Not met · 11 · evaluated, threshold not reached
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. Details ▾Hide ▴
Evidence considered
- Two published case observations
- no formal case-control data.
- Population frequency in gnomAD (v2.1: 0.002%
- v4.1: 0.002%) does not provide a reference for case-control comparison.
Still missing
- No case-control study comparing variant frequency in affected vs. unaffected individuals.
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- Residue 756 lies within the intracellular tyrosine kinase domain of FGFR1.
- Cancerhotspots.org does not identify this residue as a statistically significant hotspot.
- No CSPEC/VCEP-domain-level PM1 specification available for FGFR1.
Still missing
- No domain-level PM1 specification from ClinGen or VCEP for FGFR1.
Sources
PP1 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. Details ▾Hide ▴
Evidence considered
- One family (Provenzano 2021): variant inherited from father with equivocal C1M signs/symptoms (±).
- No multi-generational or multi-affected-family segregation data available.
Still missing
- No informative segregation data from multiple affected families.
Sources
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 1416171: Uncertain significance (3 labs)
- Likely benign (1 lab)
- Review status: criteria provided
- single submitter (not expert panel)
- No submission classifies this variant as pathogenic or likely pathogenic.
Sources
BA1 gnomAD v2.1 allele frequency is 0.00200%, well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0.00200% (far below 1% BA1 threshold)
- gnomAD v4.1 AF: 0.00198%
Sources
BS1 gnomAD v2.1 allele frequency is 0.00200%, well below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0.00200% (below 0.3% BS1 threshold)
- gnomAD v4.1 AF: 0.00198%
Sources
BS2 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. Details ▾Hide ▴
Evidence considered
- 0 homozygotes in gnomAD v2.1 and v4.1
- Father in Provenzano 2021 carried the variant with equivocal phenotype
- insufficient for healthy adult attribution.
Still missing
- No confirmed observation in a clearly healthy adult.
Sources
BS3 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. Details ▾Hide ▴
Evidence considered
- FGFR1 R756H shows significant loss of MAPK signaling in luciferase reporter assay (P<0.001).
- Functional evidence supports pathogenicity direction
- inconsistent with benign assertion.
Sources
BP1 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. Details ▾Hide ▴
Evidence considered
- FGFR1 disease mechanism includes both missense and truncating pathogenic variants (e.g.
- Hartsfield syndrome).
Sources
pvs1_gene_context
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.571 (deleterious prediction
- inconsistent with BP4)
- BayesDel: 0.254 (equivocal)
- SpliceAI max delta: 0.00 (no splice impact)
Sources
BP6 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. Details ▾Hide ▴
Evidence considered
- Fulgent Genetics (single submitter): Likely benign
- No expert panel (≥3★) benign classification
- Three other clinical laboratories classify as Uncertain significance
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense 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). Details ▾Hide ▴
Evidence considered
- Variant class is missense substitution
- not a null variant eligible for PVS1.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo evidence of a different nucleotide change at the same position leading to the same amino acid substitution (p.Arg756His) being classified as pathogenic. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide substitution at c.2267 leading to p.Arg756His identified in the case materials.
PS2 N/ANo de novo report identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observation available in case materials or literature.
PM3 N/ANo trans-configuration data for recessive disorders available. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a substitution, not a non-null protein length change. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AAutomated candidate harvesting could not confirm classic same-residue PM5 semantics; no pathogenic missense comparator variants identified at amino acid position 756. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned no eligible comparator variants at the same residue.
Sources
pm5_candidates
PM6 N/ANo de novo report identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observation available in case materials or literature.
PP2 N/APP2 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. Details ▾Hide ▴
Evidence considered
- No FGFR1 missense Z-score or constraint metric available in case materials.
Still missing
- Gene-level missense constraint data not available.
PP4 N/ANo 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. Details ▾Hide ▴
Evidence considered
- No patient-level phenotype data available in case materials.
Still missing
- Patient phenotype information not provided in case folder.
BS4 N/ANo segregation data from multiple affected family members available to assess lack of cosegregation. Details ▾Hide ▴
Evidence considered
- No multi-family segregation data available.
BP2 N/ANo data on observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans configuration data available.
BP3 N/AVariant is a substitution, not an in-frame indel in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo data on an alternate molecular basis for disease in a case carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
BP7 N/AVariant is missense (p.Arg756His), not synonymous. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous.
PS5 N/ANo 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. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide change at codon 756 producing p.Arg756His with a pathogenic assertion identified.
Identifiers
- Gene
- FGFR1
- Transcript
- NM_023110.3
- Coding (HGVS c.)
- NM_023110.3:c.2267G>A
- Protein (HGVS p.)
- NP_075598.2:p.(Arg756His)
- GRCh38
- chr8:38413943 C>T
- GRCh37
- chr8:38271461 C>T
- ClinVar
- 1416171, 66078
Gene diagram
Every interpreted variant in FGFR1, mapped onto the exon structure of NM_023110.3. Select a row to find it on the plot.
FGFR1NM_023110.3
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 FGFR1
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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
32 / 1,613,850 alleles
AF 1.98e-05 · 0 homozygotes · FAF 1.11e-05
gnomAD v2.1
5 / 249,890 alleles
AF 2e-05 · 0 homozygotes · FAF 7.04e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2e-05 · 32 / 1,613,850 alleles · 0 hom · FAF 1.1e-05
| Middle Eastern1 / 6,084 | 0.00016 |
| Remaining individuals6 / 62,480 | 9.6e-05 |
| Admixed American2 / 59,976 | 3.3e-05 |
| African/African American2 / 74,902 | 2.7e-05 |
| European (non-Finnish)20 / 1,179,956 | 1.7e-05 |
| South Asian1 / 91,060 | 1.1e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 2e-05 · 5 / 249,890 alleles · 0 hom · FAF 7e-06
| South Asian1 / 30,562 | 3.3e-05 |
| Admixed American1 / 34,486 | 2.9e-05 |
| European (non-Finnish)3 / 113,228 | 2.6e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.571
- BayesDel
- 0.254
How the predictions were used
PP3 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.571 (deleterious prediction
- >0.5 threshold)
- BayesDel: 0.254 (equivocal/borderline)
- SpliceAI max delta: 0.00 (no splice impact predicted)
Still missing
- BayesDel score is below typical damaging thresholds
- mixed in silico evidence.
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.571 (deleterious prediction
- inconsistent with BP4)
- BayesDel: 0.254 (equivocal)
- SpliceAI max delta: 0.00 (no splice impact)
Sources
BP7 N/AVariant is missense (p.Arg756His), not synonymous. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.571. BayesDel score = 0.254117.
8 paper records listed. 1 cited in the classification.
Cited in the classification
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PMID 21247312 ↗A genetic basis for functional hypothalamic amenorrhea.Caronia LM et al. · 2011 Jan 20FGFR1 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.→ PS3 Names this variant
Source detail
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.
Other recorded publications
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PMID 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.Richards S et al. · 2015ACMG/AMP standards and guidelines for the interpretation of sequence variants (Richards et al. 2015). Provides the generic variant classification framework and combination rules. Does not discuss FGFR1 or the NM_023110.3:c.2267G>A variant.Does not name this variant
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PMID 20301509 ↗Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency.Adam MP et al. · 1993GeneReview on Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. Provides general disease overview of congenital GnRH deficiency including FGFR1 as an associated gene. The specific variant NM_023110.3:c.2267G>A is not discussed.Does not name this variant
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PMID 20301702 ↗Holoprosencephaly Overview.Adam MP et al. · 1993GeneReview on Holoprosencephaly Overview. General disease overview not specific to FGFR1. The specific variant NM_023110.3:c.2267G>A is not discussed.Does not name this variant
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PMID 26937548 ↗FGFR1-Related Hartsfield Syndrome.Adam MP et al. · 1993GeneReview on FGFR1-Related Hartsfield Syndrome. Describes clinical characteristics, diagnosis, and management of FGFR1-related Hartsfield syndrome including both autosomal dominant (heterozygous) and autosomal recessive (biallelic) inheritance patterns. The specific variant NM_023110.3:c.2267G>A is not discussed in the abstract or available materials.Does not name this variant
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PMID 33337535 ↗Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes.Provenzano A et al. · 2021FGFR1 c.2267G>A (p.Arg756His) was identified as a heterozygous missense variant in a 4-year-old female with Chiari 1 malformation and trigonocephaly (Case 10). The variant was inherited from the father, who had equivocal signs and symptoms of C1M (± on MRI, ± on symptoms). The variant was classified as a pathogenic mutation associated with trigonocephaly (OMIM #190440).Names this variant
Quoted passage
Case 10 — FGFR1 c.[2267G>A];[=] p.[Arg756His];[=] Missense Trigonocephaly (#190440) rs374473310 (0.003%)
Table 1, Category A, Case 10; Results section, Category A paragraph
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PMID 35099867 ↗Encephalocraniocutaneous Lipomatosis.Adam MP et al. · 1993GeneReview on Encephalocraniocutaneous Lipomatosis. General disease overview not specific to FGFR1. The specific variant NM_023110.3:c.2267G>A is not discussed.Does not name this variant
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PMID 38648328 ↗Osteoglophonic Dysplasia.Adam MP et al. · 1993GeneReview on Osteoglophonic Dysplasia. General disease overview not specific to FGFR1. The specific variant NM_023110.3:c.2267G>A is not discussed.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
32 / 1,613,850 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
3 Uncertain significance · 1 Likely benign
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/1416171/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/8-38271461-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr8-38413943-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/8-38413943-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_023110.3%3Ac.2267…
- OncoKB ↗www.oncokb.org/gene/FGFR1/R756H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FGFR1+c.2267G%3EA
- 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
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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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
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.