VCV000000867.28 - ClinVar

NM_000507.4(FBP1):c.960_961insG (p.Ser321fs)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (7); Likely pathogenic (2)

9 out of 10 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000507.4(FBP1):c.960_961insG (p.Ser321fs)

Variation ID: 867 Accession: VCV000000867.28

Type and length

Insertion, 1 bp

Location

Cytogenetic: 9q22.32 9: 94603437-94603438 (GRCh38) [ NCBI UCSC ] 9: 97365719-97365720 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 2, 2015	Jun 20, 2026	Jan 19, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000507.4:c.960_961insG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000498.2:p.Ser321fs	frameshift
NM_001127628.2:c.960_961insG	NP_001121100.1:p.Ser321fs	frameshift
NC_000009.12:g.94603437_94603438insC
NC_000009.11:g.97365719_97365720insC
NG_008174.1:g.41812_41813insG

... more HGVS ... less HGVS

Protein change

S321fs

Other names

p.Ser321Valfs*13

Canonical SPDI

NC_000009.12:94603437::C

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00008

Exome Aggregation Consortium (ExAC) 0.00010

The Genome Aggregation Database (gnomAD), exomes 0.00012

The Genome Aggregation Database (gnomAD) 0.00021

The Genome Aggregation Database (gnomAD) 0.00022

Links

ClinGen: CA212752 OMIM: 611570.0001 dbSNP: rs757653154 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 7763253 Fig. 1 to determine the location of this allele on the current reference sequence.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FBP1		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	357	397

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Fructose-biphosphatase deficiency	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jan 19, 2026	RCV000000915.21
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Aug 1, 2022	RCV002512628.2
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 1, 2024	RCV004791191.13

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 28, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Fructose-biphosphatase deficiency	Mendelics Accession: SCV001137826.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Sep 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV005432879.12 First in ClinVar: Dec 22, 2024 Last updated: Jun 20, 2026	Comment: show FBP1: PVS1, PM2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Pathogenic (Aug 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Inborn genetic diseases	Ambry Genetics Accession: SCV003735658.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (8) PubMed: 25601412‚ 26549536‚ 28420223‚ 28776561‚ 30193751‚ 30927757‚ 7763253‚ 9382095 Comment: show The c.960_961insG (p.S321Vfs*13) alteration, located in exon 7 (coding exon 7) of the FBP1 gene, consists of an insertion of G at position 960, causing a translational frameshift with a predicted alternate stop codon after 13 amino acids. This alteration occurs at the 3' terminus of the FBP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 5% of the protein. However, premature stop codons are typically deleterious in nature. This alteration has been detected in the homozygous state, or in conjunction with another FBP1 disease-causing alteration, in multiple unrelated individuals with fructose-1,6-bisphosphatase deficiency (Kato, 2015; Lebigot, 2015; Ponzi, 2018; Li, 2017; Lee, 2019; Lu, 2017; Kikawa, 1997; Kikawa, 1995). Based on the available evidence, this alteration is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 27, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Fructose-biphosphatase deficiency (Autosomal recessive inheritance)	Department of Medical Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine Accession: SCV000537875.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Zygosity: 1 Compound Heterozygote Sex: female Platform type: High-Throughput DNA Sequencing

Pathogenic (Jul 12, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Fructose-biphosphatase deficiency	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV006058089.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Likely pathogenic (Jan 10, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Fructose-biphosphatase deficiency	3billion Accession: SCV006584371.1 First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025	Publications: PubMed (1) PubMed: 28420223 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Method: exome sequencing

Pathogenic (Jan 19, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Fructose-biphosphatase deficiency	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001389986.7 First in ClinVar: Jul 16, 2020 Last updated: Mar 07, 2026	Publications: PubMed (2) PubMed: 28420223‚ 28776561 Comment: show This sequence change creates a premature translational stop signal (p.Ser321Valfs*13) in the FBP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the FBP1 protein. This variant is present in population databases (rs757653154, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with fructose-1,6-bisphosphatase deficiency (PMID: 28420223, 28776561). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 867). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Dec 21, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Fructose-biphosphatase deficiency	Center for Molecular Medicine, Children’s Hospital of Fudan University Accession: SCV004035246.1 First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023	Observation: 1 Collection method: clinical testing Allele origin: maternal Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: maternal Affected status: yes Number of individuals with the variant: 2

Pathogenic (Dec 13, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413893.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (8) PubMed: 26549536‚ 28420223‚ 28776561‚ 30193751‚ 30927757‚ 34687058‚ 7763253‚ 9382095 Comment: show PP4, PM2_moderate, PM3_very_strong, PS3, PVS1_moderate (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1

Pathogenic (Oct 01, 1997) N Not contributing to aggregate classification	no assertion criteria provided	FRUCTOSE-1,6-BISPHOSPHATASE DEFICIENCY	OMIM Accession: SCV000021065.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 02, 2015	Publications: PubMed (2) PubMed: 7763253‚ 9382095 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In a 10-year-old Japanese girl with fructose-1,6-bisphosphatase deficiency (FBP1D; 229700), Kikawa et al. (1995) identified a homozygous 1-bp insertion (960insG) in exon 7 of the … (more) In a 10-year-old Japanese girl with fructose-1,6-bisphosphatase deficiency (FBP1D; 229700), Kikawa et al. (1995) identified a homozygous 1-bp insertion (960insG) in exon 7 of the FBP1 gene. The insertion occurred immediately following codon gly320 in the sequence of 5 Gs at nucleotide region 957-961, and resulted in a truncated protein. The patient's unaffected parents were heterozygous for the mutation. The patient had experienced recurrent attacks of metabolic acidosis and hypoglycemia since birth and had undetectable FBPase activity in leukocytes and a liver sample. Although the mutation was not well conserved, expression studies showed no FBPase activity. Kikawa et al. (1997) identified the 1-bp insertion in 16 of 22 alleles from Japanese patients with FBP1 deficiency. (less)

Comment:

The c.960_961insG (p.S321Vfs*13) alteration, located in exon 7 (coding exon 7) of the FBP1 gene, consists of an insertion of G at position 960, causing a translational frameshift with a predicted alternate stop codon after 13 amino acids. This alteration occurs at the 3' terminus of the FBP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 5% of the protein. However, premature stop codons are typically deleterious in nature. This alteration has been detected in the homozygous state, or in conjunction with another FBP1 disease-causing alteration, in multiple unrelated individuals with fructose-1,6-bisphosphatase deficiency (Kato, 2015; Lebigot, 2015; Ponzi, 2018; Li, 2017; Lee, 2019; Lu, 2017; Kikawa, 1997; Kikawa, 1995). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ser321Valfs*13) in the FBP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the FBP1 protein. This variant is present in population databases (rs757653154, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with fructose-1,6-bisphosphatase deficiency (PMID: 28420223, 28776561). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 867). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up.	Gorce M	Journal of inherited metabolic disease	2022	PMID: 34687058
Fructose-1,6-bisphosphatase deficiency presented with complex febrile convulsion.	Lee H	Neuro endocrinology letters	2019	PMID: 30927757
Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism.	Ponzi E	The Journal of pediatrics	2018	PMID: 30193751
A Chinese Adult Patient with Fructose 1,6-bisphosphatase Deficiency.	Lu JR	Chinese medical journal	2017	PMID: 28776561
Clinical and Molecular Characterization of Patients with Fructose 1,6-Bisphosphatase Deficiency.	Li N	International journal of molecular sciences	2017	PMID: 28420223
Pitfall in the Diagnosis of Fructose-1,6-Bisphosphatase Deficiency: Difficulty in Detecting Glycerol-3-Phosphate with Solvent Extraction in Urinary GC/MS Analysis.	Kato S	The Tohoku journal of experimental medicine	2015	PMID: 26549536
Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic features in French patients.	Lebigot E	Journal of inherited metabolic disease	2015	PMID: 25601412
Identification of genetic mutations in Japanese patients with fructose-1,6-bisphosphatase deficiency.	Kikawa Y	American journal of human genetics	1997	PMID: 9382095
Identification of a genetic mutation in a family with fructose-1,6- bisphosphatase deficiency.	Kikawa Y	Biochemical and biophysical research communications	1995	PMID: 7763253

Text-mined citations for rs757653154 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 20, 2026