NM_000507.4:c.960delinsGG (p.Ser321ValfsTer13) is a frameshift variant in exon 7 (last exon) of FBP1, where loss of function is an established mechanism for fructose-1,6-bisphosphatase deficiency (PVS1 at strong strength, downgraded from very strong due to predicted NMD escape per PMC6185798).1 The variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles out of >1.6 million), supporting PM2 at supporting strength.2 This variant has been classified as Pathogenic by three clinical laboratories in ClinVar (Variation ID 372364), meeting PP5 at supporting strength.3 SpliceAI predicts no significant splice impact (max delta score 0.07), and in silico pathogenicity scores are not applicable to this indel variant. PP3 and BP4 are not met.4 Under generic ACMG/AMP 2015 combination rules (PMID:25741868), one strong criterion (PVS1) and two supporting criteria (PM2, PP5) yields a classification of Likely Pathogenic.5
FBP1
Final classification
Likely Pathogenic
FBP1 c.960delinsGG · p.Ser321ValfsTer13
FBP1
NM_000507.4:c.960delinsGG (p.Ser321ValfsTer13) is a frameshift variant in exon 7 (last exon) of FBP1, where loss of function is an established mechanism for fructose-1,6-bisphosphatase deficiency (PVS1 at strong strength, downgraded from very strong due to predicted NMD escape per PMC6185798).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM2 supporting, PP5 supporting; combination = 1 strong + 2 supporting, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2PP5
Likely Pathogenic
FBP1 c.960delinsGG
PVS1 + PM2 + PP5
→
Likely Pathogenic
5
generic_acmg_combination_rules
Gene diagram
· NM_000507.4 · variants mapped to exon structure
FBP1
NM_000507.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 372364)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
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 · 5 PMIDs triaged · 5 high-priority
5papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
37142076 ↗
functional
A novel variant in the FBP1 gene causes fructose-1,6-bisphosphatase deficiency through increased ubiquitination.
Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive disorder characterized by impaired gluconeogenesis caused by mutations in the fructose-1,6-bisphosphatase 1 (FBP1) gene. The molecular mechanisms underlying FBPase deficiency caused by FBP1 mutations require investigation. Herein, we report the case of a Chinese boy with FBPase deficiency who presented with hypoglycemia, ket
BS3PP5PS3PS4
28420223 ↗
case observation
Clinical and Molecular Characterization of Patients with Fructose 1,6-Bisphosphatase Deficiency.
Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare, autosomal recessive inherited disease caused by the mutation of the FBP1 gene, the incidence is estimated to be between 1/350,000 and 1/900,000. The symptoms of affected individuals are non-specific and are easily confused with other metabolic disorders. The present study describes the clinical features of four Chinese pediatric patients w
PP5PS4
30927757 ↗
case observation
Fructose-1,6-bisphosphatase deficiency presented with complex febrile convulsion.
Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare inborn error of metabolism affecting gluconeogenesis caused by FBP1 gene mutations. It could be more fatal to infants and children when glycogen reserves are insufficient. A 4-year-old girl was admitted with complex febrile convulsion. Initial laboratory results showed hypoglycemia, metabolic acidosis, and hyperlactatemia. Plasma amino
PP5PS4
34687058 ↗
case observation
Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up.
Liver disease, occurring during pediatric or adult age, is often of undetermined cause. Some cases are probably related to undiagnosed inherited metabolic disorders. Hepatic disorders associated with fructose-1,6-bisphosphatase deficiency, a gluconeogenesis defect, are not reported in the literature. These symptoms are mainly described during acute crises, and many reports do not mention them beca
PP5PS4
Sources & reference links