G6PC3

protein-coding

glucose-6-phosphatase catalytic subunit 3, the group of Glucose 6-phosphatases, catalytic

Gene summary

This gene encodes the catalytic subunit of glucose-6-phosphatase (G6Pase). G6Pase is located in the endoplasmic reticulum (ER) and catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the last step of the gluconeogenic and glycogenolytic pathways. Mutations in this gene result in autosomal recessive severe congenital neutropenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

MANE transcript

NM_138387.4

Inheritance

ClinVar variants

P:56U:378B:239

Top phenotype

Neutropenia, severe congenital, 4, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr17:44,070,620-44,082,151

External References & Databases

Ensembl (ENSG00000141349)

Transcript & Mutation Effects

hg38 • Region Span ~11.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive severe congenital neutropenia due to G6PC3 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012930

Submitter: PanelApp Australia

autosomal recessive severe congenital neutropenia due to G6PC3 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012930

Submitter: ClinGen

G6PC3 was first reported in relation to autosomal recessive severe congenital neutropenia in 2009 (Boztug et al., PMID: 19118303). Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis with low peripheral blood absolute neutrophil counts and early onset of severe bacterial infections. Eleven variants (missense, in-frame deletion, nonsense, frameshift, and canonical splice) that have been reported in 10 probands in 2 publications (PMIDs: 19118303, 37296469) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached (if applicable). The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by mouse models, cell culture models, and in vitro functional assays. (PMIDs: 23686134, 30626647, 21385794, 25492228, and 17318259). G6PC3 deficiency results in defective neutrophil maturation and neutropenia, and has also been shown to result in defect neutrophil glycosylation. In summary, there is definitive evidence supporting the relationship between G6PC3 and autosomal recessive severe congenital neutropenia. 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 August 7, 2024 (SOP Version 10).

autosomal recessive severe congenital neutropenia due to G6PC3 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012930

Submitter: Ambry Genetics

autosomal recessive severe congenital neutropenia due to G6PC3 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012930

Submitter: Orphanet

autosomal recessive severe congenital neutropenia due to G6PC3 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012930

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neutropenia, severe congenital, 4, autosomal recessiveAR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Endocrine; Gastrointestinal; Genitourinary; Hematologic; Neurologic; Renal

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Genitourinary; Hematologic

Rationale: Antiinfectious prophylaxis (including with G-CSF) and early and aggressive treatment of infections may be beneficial; Awareness of other manifestations, including affecting the cardiac, endocrine, and urogenital systems may allow early diagnosis and treatment

Refs: 19696212; 19118303; 20799326; 20616219; 20717171; 21285905; 22050868

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to G6PC3 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 506

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiencyTotal: 411

not providedTotal: 55

not specifiedTotal: 33

G6PC3-related disorderTotal: 9

G6PC3-related disordersTotal: 6

Inherited Immunodeficiency DiseasesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138387.4. 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			1 clinvar	223 clinvar		224
missense	7 clinvar	10 clinvar	373 clinvar	16 clinvar		406
nonsense	10 clinvar	2 clinvar	1 clinvar			13
start loss	1 clinvar					1
frameshift	15 clinvar	1 clinvar	1 clinvar			17
splice donor/acceptor (+/-2bp)	3 clinvar	7 clinvar	2 clinvar			12
Total	36	20	378	239	0	673

Highest pathogenic variant AF is 0.00011413868

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138387.4	RefSeq	NP_612396.1	6	MANE Select
ENST00000269097.9	Ensembl	ENSP00000269097.3	6	MANE Select
NM_001319945.2	RefSeq	NP_001306874.1	5	Standard
NM_001384165.1	RefSeq	NP_001371094.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Adipocytokine signaling pathway - Homo sapiens (human)
Glycolysis / Gluconeogenesis - Homo sapiens (human)
Insulin resistance - Homo sapiens (human)
Starch and sucrose metabolism - Homo sapiens (human)

Biological Process

gluconeogenesis
glucose-6-phosphate transport
dephosphorylation
glucose 6-phosphate metabolic process

Molecular Function

glucose-6-phosphatase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000269097
Coding exons: 6
Length: 5607
Individuals with no LoFs: 125683
Homozygous LoFs: 0
Heterozygous LoFs: 65
Defined: 125748
p: 0.000258

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.696	161	188	0.857	0.0000112	2209
Missense (PolyPhen)		51	67.195	0.75898		802
Synonymous	-1.37	91	75.8	1.20	0.00000413	738
Loss of Function	1.47	11	17.7	0.623	9.60e-7	164

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.0010	0.0010	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00017	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. May form with the glucose-6-phosphate transporter (SLC37A4/G6PT) a ubiquitously expressed complex responsible for glucose production through glycogenolysis and gluconeogenesis. Probably required for normal neutrophil function. {ECO:0000269|PubMed:12370122, ECO:0000269|PubMed:12965222, ECO:0000269|PubMed:13129915}.;
Disease: DISEASE: Dursun syndrome (DURSS) [MIM:612541]: A disease characterized by pulmonary arterial hypertension, cardiac abnormalities including secundum-type atrial septal defect, intermittent neutropenia, lymphopenia, monocytosis and anemia. {ECO:0000269|PubMed:20799326}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.167

Intolerance Scores

LoFtool: 0.726
RVIS EVS: 0.22
RVIS percentile EVS: 68.13

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.138

Gene Damage Prediction

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