GYS1

protein-coding

glycogen synthase 1, the group of Glycosyl transferases group 1 domain containing

Gene summary

The protein encoded by this gene catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of alpha-1,4-glycoside linkages. Mutations in this gene are associated with muscle glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

Previous symbols:

MANE transcript

NM_002103.5

Inheritance

ClinVar variants

P:48U:323B:165

Top phenotype

Glycogen storage disease, type 0, muscle

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr19:48,968,130-48,993,310

External References & Databases

Ensembl (ENSG00000104812)

Transcript & Mutation Effects

hg38 • Region Span ~25.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycogen storage disease due to muscle and heart glycogen synthase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012693

Submitter: Labcorp Genetics (formerly Invitae)

glycogen storage disease due to muscle and heart glycogen synthase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012693

Submitter: PanelApp Australia

glycogen storage disease due to muscle and heart glycogen synthase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012693

Submitter: Genomics England PanelApp

glycogen storage disease due to muscle and heart glycogen synthase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012693

Submitter: Orphanet

glycogen storage disease due to muscle and heart glycogen synthase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012693

Submitter: ClinGen

*GYS1* was first reported in relation to autosomal recessive glycogen storage disease due to muscle and heart glycogen synthase deficiency in 2007 (Kollberg et al., PMID: 17928598). The primary features of this condition include exercise intolerance, tonic-clonic seizures, and sudden cardiac death. The underlying mechanism is an inability to synthesize glycogen in skeletal and cardiac muscle. Four variants (nonsense, frameshift, canonical splice site) that have been reported in three probands in three publications (PMIDs: 17928598, 19699667, 21958591) are included in this curation. The mechanism of pathogenicity is biallelic loss of function. This gene-disease association is also supported by expression studies, functional alteration in patient cells, and animal models (PMID: 15282316, 25613900, 26977394). In summary, *GYS1* is definitively associated with autosomal recessive glycogen storage disease due to muscle and heart glycogen synthase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on 9/8/2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Glycogen storage disease, type 0, muscleAR

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Individuals may manifest with findings such as hypertrophic cardiomyopathy and sudden cardiac arrest and death, and treatment with cardioprotective medications (eg, beta-blockers) has been reported as beneficial

Comments: An individual with seizures has been described, but it is not clear if this finding was primarily related to the underlying condition

Refs: 17928598; 21958591

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GYS1 variants in ClinVar

9 Conditions Cataloged

Glycogen storage disease due to muscle and heart glycogen synthase deficiencyTotal: 574

not providedTotal: 129

Inborn genetic diseasesTotal: 120

not specifiedTotal: 47

GYS1-related disorderTotal: 29

GYS1-related disordersTotal: 3

Glycogen storage diseaseTotal: 1

Fetal akinesia deformation sequence 3Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002103.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		11 clinvar	156 clinvar	5 clinvar	173
missense		1 clinvar	297 clinvar	2 clinvar	2 clinvar	302
nonsense	11 clinvar	3 clinvar	4 clinvar			18
start loss		1 clinvar	1 clinvar			2
frameshift	11 clinvar	6 clinvar	4 clinvar			21
splice donor/acceptor (+/-2bp)	3 clinvar	11 clinvar	6 clinvar			20
Total	26	22	323	158	7	536

Highest pathogenic variant AF is 0.000047088157

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002103.5	RefSeq	NP_002094.2	16	MANE Select
ENST00000323798.8	Ensembl	ENSP00000317904.3	16	MANE Select
NM_001161587.2	RefSeq	NP_001155059.1	15	Standard
ENST00000263276.6	Ensembl	ENSP00000263276.6	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Insulin resistance - Homo sapiens (human)
Starch and sucrose metabolism - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)
Glucagon signaling pathway - Homo sapiens (human)

Biological Process

glycogen biosynthetic process
heart development

Molecular Function

glycogen (starch) synthase activity
protein binding
glucose binding
protein kinase binding
glycogen synthase activity, transferring glucose-1-phosphate

Cellular Component

cytoplasm
cytosol
membrane
inclusion body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000323798
Coding exons: 16
Length: 25186
Individuals with no LoFs: 125686
Homozygous LoFs: 0
Heterozygous LoFs: 62
Defined: 125748
p: 0.000247

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.84	360	472	0.762	0.0000329	4788
Missense (PolyPhen)		139	181.16	0.76727		1856
Synonymous	0.922	183	200	0.917	0.0000150	1445
Loss of Function	3.96	14	41.5	0.337	0.00000242	422

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00055	0.00055	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.00024	0.00022	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transfers the glycosyl residue from UDP-Glc to the non- reducing end of alpha-1,4-glucan.;
Disease: DISEASE: Muscle glycogen storage disease 0 (GSD0b) [MIM:611556]: Metabolic disorder characterized by fasting hypoglycemia presenting in infancy or early childhood. The role of muscle glycogen is to provide critical energy during bursts of activity and sustained muscle work. {ECO:0000269|PubMed:17928598}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.724

Intolerance Scores

LoFtool: 0.800
RVIS EVS: -1.18
RVIS percentile EVS: 5.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

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