glycogen storage disease VI

Summary

glycogen storage disease VI (MONDO:0009294) is a disease caused by PYGL (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Israel) [Orphanet-validated]
• Causal gene: PYGL (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 293
• Phenotypes (HPO): 28
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	2.3	Israel	Validated
Prevalence at birth	1-9 / 100 000	4.8	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0006568	Increased hepatic glycogen content	Very frequent (80-99%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0001946	Ketosis	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001395	Hepatic fibrosis	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0003077	Hyperlipidemia	Occasional (5-29%)
HP:0003270	Abdominal distention	Occasional (5-29%)
HP:0003710	Exercise-induced muscle cramps	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0004913	Intermittent lactic acidemia	Occasional (5-29%)
HP:0006580	Portal fibrosis	Occasional (5-29%)
HP:0030973	Postexertional malaise	Occasional (5-29%)
HP:0000077	Abnormality of the kidney	Very rare (<1-4%)
HP:0000093	Proteinuria	Very rare (<1-4%)
HP:0001394	Cirrhosis	Very rare (<1-4%)
HP:0001402	Hepatocellular carcinoma	Very rare (<1-4%)
HP:0001639	Hypertrophic cardiomyopathy	Very rare (<1-4%)
HP:0011997	Postprandial hyperlactemia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease VI
Mondo ID	MONDO:0009294
MeSH	D006013
OMIM	232700
Orphanet	369
DOID	DOID:2754
NCIT	C126875
SNOMED CT	29291001
UMLS	C0017925
MedGen	6643
GARD	0006529
MedDRA	10053240
NORD	1241
Is cancer (heuristic)	no

Also known as: glycogen storage disease 6 · glycogen storage disease caused by mutation in PYGL · glycogen storage disease type 6 · Glycogen Storage Disease Type VI · glycogen storage disease type VI · glycogen storage disease VI · glycogenosis due to liver glycogen phosphorylase deficiency · glycogenosis type 6 · glycogenosis type VI · GSD due to liver glycogen phosphorylase deficiency · GSD type 6 · GSD type VI · GSD6 · hepatic glycogen phosphorylase deficiency · hepatic phosphorylase deficiency · hers disease · liver glycogen phosphorylase deficiency · PYGL glycogen storage disease

Data availability: 293 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism › glycogen storage disease VI

Related subtypes (23): glycogen storage disease I, glycogen storage disease due to GLUT2 deficiency, glycogen storage disease II, glycogen storage disease III, glycogen storage disease due to glycogen branching enzyme deficiency, glycogen storage disease V, glycogen storage disease VII, glycogen storage disorder due to hepatic glycogen synthase deficiency, Lafora disease, glycogen storage disease due to phosphoglycerate mutase deficiency, lethal congenital glycogen storage disease of heart, Danon disease, glycogen storage disease IXd, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, glycogen storage disease due to muscle and heart glycogen synthase deficiency, glycogen storage disease due to muscle beta-enolase deficiency, glycogen storage disease due to lactate dehydrogenase M-subunit deficiency, polyglucosan body myopathy 1 with or without immunodeficiency, glycogen storage disease due to lactate dehydrogenase deficiency, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, glycogen storage disease due to liver phosphorylase kinase deficiency, GYG1-related disorder of glycogen metabolism, glycogen storage disease IX

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

293 retrieved; paginated sample, class counts are floors:

99 uncertain significance, 72 likely benign, 36 pathogenic, 28 conflicting classifications of pathogenicity, 23 likely pathogenic, 18 benign, 8 benign/likely benign, 6 pathogenic/likely pathogenic, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
38368	NM_002863.3(PYGL):c.[1964_1969invAAAAAG;1969+1_+4delGTAC]		Pathogenic	no assertion criteria provided
1029651	NM_002863.5(PYGL):c.528+2T>C	PYGL	Pathogenic	criteria provided, single submitter
1070486	NC_000014.8:g.(?51372090)(51411141_?)del	PYGL	Pathogenic	criteria provided, single submitter
1076414	NM_002863.5(PYGL):c.1726C>T (p.Arg576Ter)	PYGL	Pathogenic	criteria provided, single submitter
11992	NM_002863.5(PYGL):c.1768+1G>A	PYGL	Pathogenic	criteria provided, multiple submitters, no conflicts
11993	NM_002863.5(PYGL):c.529-1G>C	PYGL	Pathogenic	no assertion criteria provided
11995	NM_002863.5(PYGL):c.1131C>G (p.Asn377Lys)	PYGL	Pathogenic	no assertion criteria provided
11996	NM_002863.5(PYGL):c.1620+1G>A	PYGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686118	NM_002863.5(PYGL):c.1404-1G>A	PYGL	Pathogenic	criteria provided, single submitter
1799523	NM_002863.5(PYGL):c.198del (p.Arg67fs)	PYGL	Pathogenic	criteria provided, single submitter
189242	NM_002863.5(PYGL):c.25_44dup (p.Ser15fs)	PYGL	Pathogenic	criteria provided, multiple submitters, no conflicts
1935779	NM_002863.5(PYGL):c.1475G>A (p.Trp492Ter)	PYGL	Pathogenic	criteria provided, multiple submitters, no conflicts
194626	NM_002863.5(PYGL):c.1947C>A (p.Tyr649Ter)	PYGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1987284	NM_002863.5(PYGL):c.647G>A (p.Trp216Ter)	PYGL	Pathogenic	criteria provided, single submitter
1988522	NM_002863.5(PYGL):c.514C>T (p.Arg172Ter)	PYGL	Pathogenic	criteria provided, single submitter
2075738	NM_002863.5(PYGL):c.179_197del (p.Val60fs)	PYGL	Pathogenic	criteria provided, single submitter
21327	NM_002863.5(PYGL):c.1195C>T (p.Arg399Ter)	PYGL	Pathogenic	criteria provided, single submitter
21328	NM_002863.5(PYGL):c.1366G>A (p.Val456Met)	PYGL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21337	NM_002863.5(PYGL):c.280C>T (p.Arg94Ter)	PYGL	Pathogenic	criteria provided, multiple submitters, no conflicts
21339	NM_002863.5(PYGL):c.698G>A (p.Gly233Asp)	PYGL	Pathogenic	criteria provided, single submitter
2148422	NM_002863.5(PYGL):c.1964_1969+4delinsGAAAAA	PYGL	Pathogenic	criteria provided, multiple submitters, no conflicts
2627510	NM_002863.5(PYGL):c.528+1G>A	PYGL	Pathogenic	criteria provided, single submitter
2815716	NM_002863.5(PYGL):c.1228A>T (p.Lys410Ter)	PYGL	Pathogenic	criteria provided, single submitter
3385228	NM_002863.5(PYGL):c.730C>T (p.Leu244Phe)	PYGL	Pathogenic	criteria provided, single submitter
3701206	NM_002863.5(PYGL):c.1778_1781del (p.Lys593fs)	PYGL	Pathogenic	criteria provided, single submitter
3720984	NM_002863.5(PYGL):c.808C>T (p.Arg270Ter)	PYGL	Pathogenic	criteria provided, single submitter
3727125	NM_002863.5(PYGL):c.324del (p.Cys109fs)	PYGL	Pathogenic	criteria provided, single submitter
38367	NM_002863.5(PYGL):c.1016A>G (p.Asn339Ser)	PYGL	Pathogenic	no assertion criteria provided
4771897	NM_002863.5(PYGL):c.217C>T (p.Gln73Ter)	PYGL	Pathogenic	criteria provided, single submitter
548489	NM_002863.5(PYGL):c.298_307del (p.Met100fs)	PYGL	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PYGL	Definitive	Autosomal recessive	glycogen storage disease VI	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PYGL	Orphanet:369	Glycogen storage disease due to liver glycogen phosphorylase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PYGL	HGNC:9725	ENSG00000100504	P06737	Glycogen phosphorylase, liver form	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PYGL	Glycogen phosphorylase, liver form	Allosteric enzyme that catalyzes the rate-limiting step in glycogen catabolism, the phosphorolytic cleavage of glycogen to produce glucose-1-phosphate, and plays a central role in maintaining cellular and organismal glucose homeostasis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PYGL	Enzyme (other)	yes	2.4.1.1	Glyco_trans_35, Glycg_phsphrylas, Pyridoxal_P_attach_site

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PYGL	255	ubiquitous	marker	blood, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PYGL	2,733

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PYGL	P06737	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycogen breakdown (glycogenolysis)	1	761.3×	0.003	PYGL
Neutrophil degranulation	1	23.1×	0.043	PYGL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycogen catabolic process	1	1203.7×	0.002	PYGL
necroptotic process	1	1053.2×	0.002	PYGL
glycogen metabolic process	1	526.6×	0.003	PYGL
response to bacterium	1	193.7×	0.006	PYGL
glucose homeostasis	1	130.6×	0.008	PYGL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PYGL	3	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALVOCIDIB	3	PYGL
QUERCETIN	3	PYGL
AFEGOSTAT	2	PYGL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PYGL	58	Binding:58

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PYGL	2.4.1.1	glycogen phosphorylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ALVOCIDIB	3	PYGL
QUERCETIN	3	PYGL
AFEGOSTAT	2	PYGL

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	PYGL
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04454216	Not specified	RECRUITING	GSD VI and GSD IX Natural History
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)