GFPT1

protein-coding

glutamine--fructose-6-phosphate transaminase 1

Gene summary

This gene encodes the first and rate-limiting enzyme of the hexosamine pathway and controls the flux of glucose into the hexosamine pathway. The product of this gene catalyzes the formation of glucosamine 6-phosphate. [provided by RefSeq, Sep 2008]

Previous symbols:

GFPT

MANE transcript

NM_001244710.2

Inheritance

ClinVar variants

P:53U:168B:95

Top phenotype

Myasthenic syndrome, congenital 12

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr2:69,319,780-69,387,250

External References & Databases

Ensembl (ENSG00000198380)

Transcript & Mutation Effects

hg38 • Region Span ~67.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital myasthenic syndrome 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012518

Submitter: PanelApp Australia

congenital myasthenic syndrome 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012518

Submitter: Genomics England PanelApp

congenital myasthenic syndrome 12MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012518

Submitter: Ambry Genetics

congenital myasthenic syndrome 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012518

Submitter: Labcorp Genetics (formerly Invitae)

congenital myasthenic syndrome 12DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012518

Submitter: ClinGen

GFPT1 was first reported in relation to autosomal recessive congenital myasthenic syndrome 12 in 2011 (Senderek et al., PMID: 21310273). Twelve variants (missense, nonsense, frameshift, splicing) that have been reported in 8 probands in 2 publications (PMIDs: 21310273, 23794683) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Congenital myasthenic syndrome 12 is characterized by limb-girdle muscle weakness and tubular aggregates on muscle biopsies. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is also supported by the biochemical function of GFPT1, which is involved in the hexosamine biosynthesis pathway that serves as a source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans, animal models that recapitulate disease, and expression in skeletal muscle (PMIDs: 21310273, 29905857, 11679416). In summary, there is definitive evidence supporting the relationship between GFPT1 and to autosomal recessive congenital myasthenic syndrome 12.This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date July 3, 2024 (SOP Version 10).

congenital myasthenic syndromes with glycosylation defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018144

Submitter: Orphanet

congenital myasthenic syndrome 12DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012518

Submitter: Illumina

Clinical Genomic Database (CGD)

Myasthenic syndrome, congenital 12AR

Manifestation: Musculoskeletal; Neurologic

Intervention: Musculoskeletal; Pharmacogenomic

Rationale: Acetylcholinesterase inhibitors have been shown to result in a favorable treatment response; Avoidance of certain agents involved in neuromuscular transmission is indicated (eg, ciprofloxacin, chloroquine, lithium, phenytoin, beta-blockers, procainamide); Additional neurologic monitoring in pregnancy may be beneficial

Refs: 8664562; 12467753; 21310273; 23108489

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GFPT1 variants in ClinVar

13 Conditions Cataloged

Congenital myasthenic syndrome 12Total: 386

not providedTotal: 75

not specifiedTotal: 30

Inborn genetic diseasesTotal: 30

GFPT1-related disorderTotal: 9

Congenital myasthenic syndromeTotal: 7

Congenital myasthenic syndrome 4CTotal: 3

Hereditary ataxiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001244710.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	92 clinvar	2 clinvar	97
missense	4 clinvar	13 clinvar	156 clinvar	1 clinvar		174
nonsense	7 clinvar	4 clinvar	1 clinvar			12
start loss	1 clinvar					1
frameshift	11 clinvar	4 clinvar				15
splice donor/acceptor (+/-2bp)	2 clinvar	7 clinvar	8 clinvar			17
Total	25	28	168	93	2	316

Highest pathogenic variant AF is 0.000056383196

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001244710.2	RefSeq	NP_001231639.1	20	MANE Select
ENST00000357308.9	Ensembl	ENSP00000349860.4	20	MANE Select
NM_002056.4	RefSeq	NP_002047.2	19	Standard
ENST00000361060.5	Ensembl	ENSP00000354347.4	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
gfpt1	Danio rerio	Structure: slow muscle cell Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

gfpt1

Danio rerio

Structure: slow muscle cell

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Insulin resistance - Homo sapiens (human)
Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)
Sialuria or French Type Sialuria
Sialuria or French Type Sialuria

Biological Process

fructose 6-phosphate metabolic process
UDP-N-acetylglucosamine metabolic process
UDP-N-acetylglucosamine biosynthetic process
energy reserve metabolic process
protein N-linked glycosylation

Molecular Function

glutamine-fructose-6-phosphate transaminase (isomerizing) activity
carbohydrate derivative binding

Cellular Component

cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357308
Coding exons: 20
Length: 67478
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.35	151	394	0.383	0.0000220	4617
Missense (PolyPhen)		30	155.75	0.19262		1850
Synonymous	1.04	112	127	0.883	0.00000641	1300
Loss of Function	4.92	8	42.7	0.187	0.00000250	488

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000063	0.000062	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins. Regulates the circadian expression of clock genes ARNTL/BMAL1 and CRY1.;

Recessive Scores

pRec: 0.509

Intolerance Scores

LoFtool: 0.332
RVIS EVS: -0.49
RVIS percentile EVS: 22.09

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.985

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium