GeneBe

PYGL

protein-coding

glycogen phosphorylase L, the group of Glycogen phosphorylases

Gene summary

This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2011]

MANE transcript

NM_002863.5

Inheritance

AR

ClinVar variants

P:88U:189B:85

Top phenotype

Glycogen storage disease VI

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr14:50,857,891-50,944,483

External References & Databases

Ensembl (ENSG00000100504)NCBI Gene (5836)OMIM (613741)HGNC:9725GenCCUniProt (P06737)AlphaFoldClinVar (PYGL)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~86.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease VIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009294

Submitter: G2P

glycogen storage disease VIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009294

Submitter: ClinGen

**PYGL, glycogen storage disease VI (MONDO:0009294), autosomal recessive** PYGL was first described as a glycogen storage disorder (GSD)-causing gene in 1986 (Newgard et al. 1986, PMID: 2877458). The specific disease entity, glycogen storage disorder VI (also referred to as Hers disease) (MONDO:0009294, OMIM:613741), is one of at least 15 different glycogen storage disorders which affect the body and its ability to correctly use or store glycogen. Some of the most common patient phenotypes are: Hepatomegaly, hypoglycemia, growth retardation, weight retardation, elevated hepatic transaminase levels, accumulation of glycogen in the liver cells/hepatocytes and response to the use of cornstarch supplements to prevent hypoglycemia. Twenty-six variants: (Canonical Splice Site (8 variants), Missense (10 variants), Nonsense (6 variants), Multi-Exon Deletion (1 variant), Frameshift (1 variant)) that have been reported in 25 probands and 1 family in 11 publications (PMIDs: 9529348, 9536091, 32268899, 33879691, 32961316, 28984260, 32892177, 34026552, 36105079, 32374048, 37264426) are included in this curation. Many of the probands were diagnosed during childhood after experiencing symptoms including hepatomegaly, hypoglycemia, growth retardation, weight retardation or elevated transaminase and aminotransferase levels. However, their symptoms were largely able to be controlled through dietary changes or ingesting dosages of cornstarch. Siblings of the probands were also found to be affected to varying degrees of severity. Overall, the mechanism of pathogenicity appears to be loss of function as shown in the probands. This gene-disease relationship is also supported by multiple forms of experimental evidence such as Expression A (Quantity: 1), Biochemical Function B (Quantity: 1), Biochemical Function A (Quantity: 1) and Non-Human Model: Mouse (Quantity: 1) (PMIDs: 25613900, 34939084, 30659246 and 31701076). First, ProteinAtlas data showed high levels of expression of PYGL in the liver, which is consistent with the liver-related features of GSD0 (PMID:25613900). Next, Chen et al. 2022 (34939084) documented that the addition of wild-type PYGL to HEK293T cells caused a dramatic increase in glycogen phosphorylase activity (Figure 6B). Kishnani et al 2019 (PMID: 30659246) describes how both PYGL and PHKG2 are involved with glycogen breakdown in the liver. Additionally, PHKG2 probands have very similar phenotypes to PYGL including hepatomegaly, growth retardation, elevated serum transaminases, increased liver glycogen and liver fibrosis. PHKG2 was classified as having a "definitive" relationship with glycogen storage disease IXc by the General Inborn Errors of Metabolism GCEP. Lastly, Wilson et al 2019 describes a mouse model. This mouse model recapitulates many of the phenotypes seen in the human probands. The mouse model had hepatomegaly which recapitulates the same phenotype that is seen in the human proband. Both the mouse model and the human patients displayed abnormal hepatic glycogen storage. Additionally, the model also displayed hypoglycemia, just like the human probands (PMID: 31701076). In conclusion, PYGL is definitively associated with glycogen storage disorder VI (also referred to as Hers disease). This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time. This classification was approved by the General IEM GCEP on September 27th, 2024 (SOP Version 10).

glycogen storage disease VIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009294

Submitter: Ambry Genetics

glycogen storage disease VISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009294

Submitter: PanelApp Australia

glycogen storage disease VISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009294

Submitter: Orphanet

glycogen storage disease VISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009294

Submitter: Labcorp Genetics (formerly Invitae)

glycogen storage disease VISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009294

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Glycogen storage disease VIAR

Manifestation: Biochemical

Intervention: Biochemical

Rationale: The condition can include manifestations suc has hypoglycemia, ketosis, and growth retardation, and recommendations for care include laboratory-based monitoring (eg, including liver function tests, glucose, and ketones), radiological monitoring (abdominal imaging), and nutritional recommendations and avoidance of certain medications in order to help improve metabolic to control and prevent the primary complications; Specific care during pregnancy has been recommended

Refs: 13646331; 5904467; 9529348; 9536091; 17705025; 20301788; 21646031; 25266922; 30659246Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PYGL variants in ClinVar

6 Conditions Cataloged
Glycogen storage disease, type VITotal: 280
Inborn genetic diseasesTotal: 92
not providedTotal: 89
not specifiedTotal: 44
PYGL-related disorderTotal: 32
Glycogen storage diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002863.5. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
4
clinvar
68
clinvar
1
clinvar
 74
missense
4
clinvar
21
clinvar
180
clinvar
14
clinvar
2
clinvar
 221
nonsense
12
clinvar
10
clinvar
1
clinvar
 23
start loss
1
clinvar
 1
frameshift
10
clinvar
10
clinvar
 20
splice donor/acceptor (+/-2bp)
11
clinvar
8
clinvar
4
clinvar
 23
Total3751189823362

Highest pathogenic variant AF is 0.0001455936

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002863.5RefSeqNP_002854.320MANE Select
ENST00000216392.8EnsemblENSP00000216392.720MANE Select
NM_001163940.2RefSeqNP_001157412.119Standard
ENST00000532462.5EnsemblENSP00000431657.120Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Insulin resistance - Homo sapiens (human)
  • Starch and sucrose metabolism - Homo sapiens (human)
  • Glucagon signaling pathway - Homo sapiens (human)
  • Necroptosis - Homo sapiens (human)
  • Insulin signaling pathway - Homo sapiens (human)

Biological Process

  • glycogen metabolic process
  • glycogen catabolic process
  • 5-phosphoribose 1-diphosphate biosynthetic process
  • response to bacterium
  • glucose homeostasis

Molecular Function

  • purine nucleobase binding
  • protein binding
  • ATP binding
  • glucose binding
  • drug binding

Cellular Component

  • extracellular region
  • cytoplasm
  • cytosol
  • secretory granule lumen
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000216392
Coding exons
20
Length
86846
Individuals with no LoFs
41757
Homozygous LoFs
26796
Heterozygous LoFs
57195
Defined
125748
p
0.424
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.2034784661.030.00002545610
Missense (PolyPhen)246239.071.0292934
Synonymous0.2971771820.9720.00001031601
Loss of Function1.743345.70.7220.00000259525

Population LoF Frequency

PopulationCAFp-valueStatus
African0.660.66notable
Latino/Admixed American0.650.64notable
Ashkenazi Jewish0.340.33notable
East Asian0.610.61notable
Finnish0.360.36notable
European (Non-Finnish)0.340.34notable
South Asian0.450.44notable
Other0.410.41notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.;
Disease
DISEASE: Glycogen storage disease 6 (GSD6) [MIM:232700]: A metabolic disorder characterized by mild to moderate hypoglycemia, mild ketosis, growth retardation, and prominent hepatomegaly. Heart and skeletal muscle are not affected. {ECO:0000269|PubMed:9529348}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.423

Intolerance Scores

LoFtool
0.0522
RVIS EVS
0.21
RVIS percentile EVS
67.5

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.992

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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