SLC37A4

protein-coding

solute carrier family 37 member 4, the group of Solute carrier family 37

Gene summary

This gene regulates glucose-6-phosphate transport from the cytoplasm to the lumen of the endoplasmic reticulum, in order to maintain glucose homeostasis. It also plays a role in ATP-mediated calcium sequestration in the lumen of the endoplasmic reticulum. Mutations in this gene have been associated with various forms of glycogen storage disease. Alternative splicing in this gene results in multiple transcript variants.[provided by RefSeq, Aug 2009]

Previous symbols:

G6PT1
G6PT2
G6PT3

MANE transcript

N/A

Inheritance

AR, AD

ClinVar variants

—

Top phenotype

Glycogen storage disease Ib; Glycogen storage disease Ic; Glycogen storage disease Id; Congenital disorder of glycosylation, type IIw

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr11:119,023,751-119,030,906

External References & Databases

Ensembl (ENSG00000137700)

Transcript & Mutation Effects

hg38 • Region Span ~7.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease IbSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009288

Submitter: Genomics England PanelApp

congenital disorder of glycosylation, type IIwSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030437

Submitter: Labcorp Genetics (formerly Invitae)

congenital disorder of glycosylation, type IIwSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030437

Submitter: PanelApp Australia

glycogen storage disease IbDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009288

Submitter: G2P

glycogen storage disease IbDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009288

Submitter: Natera

congenital disorder of glycosylation, type IIwMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030437

Submitter: Natera

glycogen storage disease type 1 due to SLC37A4 mutationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0023258

Submitter: Myriad Women's Health

glycogen storage disease IbSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009288

Submitter: PanelApp Australia

glycogen storage disease IbSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009288

Submitter: PanelApp Australia

glycogen storage disease IbSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009288

Submitter: Labcorp Genetics (formerly Invitae)

glycogen storage disease IbSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009288

Submitter: Genomics England PanelApp

congenital disorder of glycosylation, type IIwDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030437

Submitter: G2P

Clinical Genomic Database (CGD)

Glycogen storage disease Ib; Glycogen storage disease Ic; Glycogen storage disease Id; Congenital disorder of glycosylation, type IIwAR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal; Oncologic; Renal

Intervention: Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Gastrointestinal; Oncologic; Renal

Rationale: In Glycogen storage disease, dietary measures can be beneficial allow optimal glucose levels and promote growth and development (additionally, specific carbohydrate sources should be limited); Allopurinol to prevent gout and lipid-lowering medications to prevent hyperlipidemia may be necessary when dietary therapy is ineffective; Citrate supplementation and ACE inhibitors may help prevent development of decrease renal complications, though renal transplant may ultimately be necessary; Surveillance for and treatment of hepatic neoplasms (including liver transplant in some) can be beneficial; G-CSF may be beneficial due to recurrent infections; Individuals with Congenital disorder of glycosylation, type IIw have been described to have hepatic dysfunction, including involving coagulopathy, as well as congenital cardiac anomalies requiring surgical interventions, and awareness may allow early diagnosis and management

Refs: 4300573; 212064; 6928812; 6578929; 6298622; 6309784; 3860000; 3459848; 3464427; 2311631; 1719175; 1375344; 8319729; 273986; 8758135; 9428641; 9758626; 9686363; 10931421; 12576310; 20301489; 21575371; 21599942; 21629566; 31536830; 32884905; 33728255; 33964207

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC37A4 variants in ClinVar

2 Conditions Cataloged

Glucose-6-phosphate transport defectTotal: 6

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript . 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
synonymous
missense
nonsense
start loss
frameshift
splice donor/acceptor (+/-2bp)
Total	0	0	0	0	0

Highest pathogenic variant AF is 0.00000657142

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001164277.2	RefSeq	NP_001157749.1	9	Standard
NM_001164278.2	RefSeq	NP_001157750.1	10	Standard
NM_001164279.2	RefSeq	NP_001157751.1	8	Standard
NM_001164280.2	RefSeq	NP_001157752.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Carbohydrate digestion and absorption - Homo sapiens (human)
Mitochondrial Electron Transport Chain
Gluconeogenesis
Glycogenosis, Type IA. Von gierke disease
Glycogenosis, Type IC

Biological Process

glucose metabolic process
gluconeogenesis
carbohydrate transport
glucose-6-phosphate transport
phosphate ion transmembrane transport

Molecular Function

transporter activity
glucose-6-phosphate transmembrane transporter activity
glucose 6-phosphate:inorganic phosphate antiporter activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
membrane
integral component of membrane
integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357590
Coding exons: 10
Length: 6793
Individuals with no LoFs: 377
Homozygous LoFs: 124265
Heterozygous LoFs: 0
Defined: 124642
p: 0.945

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.00226	249	249	1.00	0.0000132	2868
Missense (PolyPhen)		65	75.078	0.86577		848
Synonymous	-0.455	104	98.3	1.06	0.00000508	929
Loss of Function	1.98	11	20.7	0.531	9.83e-7	224

Population LoF Frequency

Population	CAF	p-value	Status
African	1.0	0.94	notable
Latino/Admixed American	1.0	0.95	notable
Ashkenazi Jewish	1.0	0.95	notable
East Asian	1.0	0.97	notable
Finnish	1.0	0.96	notable
European (Non-Finnish)	1.0	0.94	notable
South Asian	1.0	0.95	notable
Other	1.0	0.95	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum. Transports cytoplasmic glucose-6- phosphate into the lumen of the endoplasmic reticulum and translocates inorganic phosphate into the opposite direction. Forms with glucose-6-phosphatase the complex responsible for glucose production through glycogenolysis and gluconeogenesis. Hence, it plays a central role in homeostatic regulation of blood glucose levels. {ECO:0000269|PubMed:10026167, ECO:0000269|PubMed:21949678}.;
Disease: DISEASE: Glycogen storage disease 1C (GSD1C) [MIM:232240]: A metabolic disorder characterized by impairment of terminal steps of glycogenolysis and gluconeogenesis. Patients manifest a wide range of clinical symptoms and biochemical abnormalities, including hypoglycemia, severe hepatomegaly due to excessive accumulation of glycogen, kidney enlargement, growth retardation, lactic acidemia, hyperlipidemia, and hyperuricemia. {ECO:0000269|PubMed:10482962, ECO:0000269|PubMed:9758626}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glycogen storage disease 1D (GSD1D) [MIM:232240]: A metabolic disorder characterized by impairment of terminal steps of glycogenolysis and gluconeogenesis. Patients manifest a wide range of clinical symptoms and biochemical abnormalities, including hypoglycemia, severe hepatomegaly due to excessive accumulation of glycogen, kidney enlargement, growth retardation, lactic acidemia, hyperlipidemia, and hyperuricemia. {ECO:0000269|PubMed:9758626}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.325

Essentials

Indispensability pred.: N
Indispensability score: 0.367

Gene Damage Prediction

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