Glycogen storage disease due to muscle and heart glycogen synthase deficiency

Summary

Glycogen storage disease due to muscle and heart glycogen synthase deficiency (MONDO:0012693) is a disease caused by GYS1 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GYS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 611
• Phenotypes (HPO): 11
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0002875	Exertional dyspnea	Very frequent (80-99%)
HP:0003326	Myalgia	Very frequent (80-99%)
HP:0001279	Syncope	Frequent (30-79%)
HP:0003200	Ragged-red muscle fibers	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0003756	Skeletal myopathy	Frequent (30-79%)
HP:0012270	Decreased muscle glycogen content	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001645	Sudden cardiac death	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0003551	Difficulty climbing stairs	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycogen storage disease due to muscle and heart glycogen synthase deficiency
Mondo ID	MONDO:0012693
MeSH	C566917
OMIM	611556
Orphanet	137625
SNOMED CT	725027004
UMLS	C1969054
MedGen	409741
GARD	0010760
Is cancer (heuristic)	no

Also known as: glycogen storage disease 0, muscle · glycogen storage disease due to glycogen synthase deficiency of heart · glycogen storage disease type 0, muscle · glycogen storage disease type 0b · glycogenosis due to muscle and heart glycogen synthase deficiency · glycogenosis type 0b · GSD due to muscle and heart glycogen synthase deficiency · GSD type 0b · GSD0B · heart glycogen storage disease due to glycogen synthase deficiency

Data availability: 611 ClinVar variants · 4 GenCC gene-disease records.

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 due to muscle and heart glycogen synthase deficiency

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 VI, 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 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

600 retrieved; paginated sample, class counts are floors:

270 uncertain significance, 240 likely benign, 31 pathogenic, 20 conflicting classifications of pathogenicity, 15 benign, 10 likely pathogenic, 10 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064610	NM_002103.5(GYS1):c.1646-1_1647del	GYS1	Pathogenic	criteria provided, single submitter
1069149	NM_002103.5(GYS1):c.699_700del (p.Arg236fs)	GYS1	Pathogenic	criteria provided, single submitter
1073960	NC_000019.9:g.(?49485502)(49486104_?)del	GYS1	Pathogenic	criteria provided, single submitter
1074189	NM_002103.5(GYS1):c.913C>T (p.Gln305Ter)	GYS1	Pathogenic	criteria provided, single submitter
128236	NM_002103.5(GYS1):c.162_163del (p.Asp56fs)	GYS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1430475	NM_002103.5(GYS1):c.546G>A (p.Trp182Ter)	GYS1	Pathogenic	criteria provided, single submitter
1432649	NM_002103.5(GYS1):c.405_420del (p.Asp135fs)	GYS1	Pathogenic	criteria provided, single submitter
1433467	NM_002103.5(GYS1):c.929del (p.Gly310fs)	GYS1	Pathogenic	criteria provided, single submitter
1455547	NC_000019.9:g.(?49477450)(49478010_?)del	GYS1	Pathogenic	criteria provided, single submitter
1466408	NM_002103.5(GYS1):c.678+2T>G	GYS1	Pathogenic	criteria provided, single submitter
16057	NM_002103.5(GYS1):c.1384C>T (p.Arg462Ter)	GYS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1948472	NM_002103.5(GYS1):c.359del (p.Gly120fs)	GYS1	Pathogenic	criteria provided, single submitter
2138317	NM_002103.5(GYS1):c.1230-2A>G	GYS1	Pathogenic	criteria provided, single submitter
2146827	NM_002103.5(GYS1):c.7_8del (p.Leu3fs)	GYS1	Pathogenic	criteria provided, single submitter
2182696	NM_002103.5(GYS1):c.721C>T (p.Arg241Ter)	GYS1	Pathogenic	criteria provided, single submitter
2416446	NM_002103.5(GYS1):c.583C>T (p.Arg195Ter)	GYS1	Pathogenic	criteria provided, single submitter
2705242	NM_002103.5(GYS1):c.1192_1193insCAAGG (p.Glu398fs)	GYS1	Pathogenic	criteria provided, single submitter
2770149	NM_002103.5(GYS1):c.169G>T (p.Glu57Ter)	GYS1	Pathogenic	criteria provided, single submitter
2818809	NM_002103.5(GYS1):c.1539del (p.Tyr514fs)	GYS1	Pathogenic	criteria provided, single submitter
3248454	NC_000019.9:g.(?49494539)(49494760_?)del	GYS1	Pathogenic	criteria provided, single submitter
3248455	NC_000019.9:g.(?49484767)(49486114_?)del	GYS1	Pathogenic	criteria provided, single submitter
3347888	NM_002103.5(GYS1):c.1716_1717del (p.Tyr572_Ser573delinsTer)	GYS1	Pathogenic	criteria provided, single submitter
3618810	NM_002103.5(GYS1):c.502C>T (p.Gln168Ter)	GYS1	Pathogenic	criteria provided, single submitter
3717524	NM_002103.5(GYS1):c.1234del (p.Ser412fs)	GYS1	Pathogenic	criteria provided, single submitter
3725421	NM_002103.5(GYS1):c.1358C>G (p.Ser453Ter)	GYS1	Pathogenic	criteria provided, single submitter
4086079	NM_002103.5(GYS1):c.630G>C (p.Gly210=)	GYS1	Pathogenic	no assertion criteria provided
4086080	NM_002103.5(GYS1):c.678+1G>C	GYS1	Pathogenic	no assertion criteria provided
422359	NM_002103.5(GYS1):c.160dup (p.Thr54fs)	GYS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4761937	NM_002103.5(GYS1):c.198dup (p.Pro67fs)	GYS1	Pathogenic	criteria provided, single submitter
4798670	NM_002103.5(GYS1):c.1793G>A (p.Trp598Ter)	GYS1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
GYS1	Strong	Autosomal recessive	glycogen storage disease due to muscle and heart glycogen synthase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GYS1	Orphanet:137625	Glycogen storage disease due to muscle and heart glycogen synthase 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
GYS1	HGNC:4706	ENSG00000104812	P13807	Glycogen [starch] synthase, muscle	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GYS1	Glycogen [starch] synthase, muscle	Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme.

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)
GYS1	Enzyme (other)	yes	2.4.1.11	Glycogen_synth

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
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GYS1	257	ubiquitous	marker	hindlimb stylopod muscle, apex of heart, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GYS1	2,900

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GYS1	P13807	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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 storage disease type XV (GYG1)	1	5710.0×	4e-04	GYS1
Glycogen storage disease type 0 (muscle GYS1)	1	5710.0×	4e-04	GYS1
Myoclonic epilepsy of Lafora	1	1268.9×	0.001	GYS1
Glycogen synthesis	1	815.7×	0.001	GYS1

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 biosynthetic process	1	936.2×	0.002	GYS1
heart development	1	78.8×	0.013	GYS1

Therapeutics

Drug target analysis

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

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
GYS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GYS1	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GYS1	2.4.1.11	glycogen(starch) synthase

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

0 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.

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	0
C	Druggable family + PDB, no drug	1	GYS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GYS1	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study