Glycogen storage disease: genes and variants

Genes linked to Glycogen storage disease

• GAA: Lysosomal alpha-glucosidase

  It degrades lysosomal glycogen to free glucose. Biallelic loss-of-function variants cause Pompe disease, ranging from severe infantile cardiomyopathy to later-onset progressive skeletal and respiratory muscle weakness.

  214 disease-causing and 801 uncertain variants in GAA are linked to Glycogen storage disease.

• G6PC1: Glucose-6-phosphatase catalytic subunit 1

  It catalyzes the final step of hepatic and renal glucose production by hydrolyzing glucose-6-phosphate to free glucose. Biallelic loss-of-function variants cause glycogen storage disease type Ia, with fasting hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, and hepatomegaly.

  5 disease-causing and 1 uncertain variants in G6PC1 are linked to Glycogen storage disease.

• SLC37A4: Glucose-6-phosphate exchanger SLC37A4

  It transports glucose-6-phosphate into the endoplasmic reticulum so glucose-6-phosphatase can release free glucose during fasting. Biallelic loss-of-function variants cause glycogen storage disease type Ib, with fasting hypoglycemia, hepatomegaly, neutropenia, and inflammatory bowel disease.

  1 disease-causing and 7 uncertain variants in SLC37A4 are linked to Glycogen storage disease.

• ALDOB: Fructose-bisphosphate aldolase B

  It cleaves fructose-1-phosphate and fructose-1,6-bisphosphate during fructose and glucose metabolism in liver, kidney, and intestine. Biallelic loss-of-function variants cause hereditary fructose intolerance, in which fructose ingestion can trigger hypoglycemia, vomiting, and liver injury.

  1 disease-causing and 0 uncertain variants in ALDOB are linked to Glycogen storage disease.

Known disease-causing variants in Glycogen storage disease

Showing 60 of 221.

Uncertain variants in Glycogen storage disease that look disease-causing

Which prediction tools work for Glycogen storage disease

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MetaLR: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 92 out of 100
• CADD: 90 out of 100
• phyloP: 76 out of 100

Same protein, different disease

• Glycogen storage disease due to glucose-6-phosphatase deficiency is also caused by G6PC1 variants; they fall mostly in different places as the Glycogen storage disease variants (64 disease-causing).
• Glucose-6-phosphate transport defect is also caused by SLC37A4 variants; they fall mostly in different places as the Glycogen storage disease variants (30 disease-causing).
• Phosphate transport defect is also caused by SLC37A4 variants; they fall mostly in different places as the Glycogen storage disease variants (7 disease-causing).
• Congenital disorder of glycosylation, type IIw is also caused by SLC37A4 variants; they fall mostly in different places as the Glycogen storage disease variants (6 disease-causing).
• Hereditary fructosuria is also caused by ALDOB variants; they fall mostly in different places as the Glycogen storage disease variants (19 disease-causing).

Diseases related to Glycogen storage disease

• Glycogen storage disease due to glucose-6-phosphatase deficiency, also linked to G6PC1 and SLC37A4
• Type 2 diabetes mellitus, also linked to GAA
• Glucose-6-phosphate transport defect, also linked to SLC37A4
• Hereditary fructosuria, also linked to ALDOB
• Congenital disorder of glycosylation, type IIw, also linked to SLC37A4
• Phosphate transport defect, also linked to SLC37A4

Frequently asked questions

Which genes are linked to Glycogen storage disease?

In CATVariant, Glycogen storage disease is linked to 4 analyzed proteins: GAA (Lysosomal alpha-glucosidase), G6PC1 (Glucose-6-phosphatase catalytic subunit 1), SLC37A4 (Glucose-6-phosphate exchanger SLC37A4) and ALDOB (Fructose-bisphosphate aldolase B).

How many genetic variants are linked to Glycogen storage disease?

1,063 variants: 221 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 809 are of uncertain significance or have conflicting reports.

Which uncertain variants in Glycogen storage disease look disease-causing?

45 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GAA G638E, GAA C108Y, GAA R600P, GAA G377S and GAA G576D. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Glycogen storage disease?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.92, based on 179 disease-causing and 31 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

Download every variant as CSV · Browse all diseases · Methods · About the Center