Lethal congenital glycogen storage disease of heart

Summary

Lethal congenital glycogen storage disease of heart (MONDO:0009867) is a disease caused by PRKAG2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PRKAG2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 930

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal congenital glycogen storage disease of heart
Mondo ID	MONDO:0009867
MeSH	C564888
OMIM	261740
Orphanet	439854
DOID	DOID:0090101
UMLS	C1849813
MedGen	337919
GARD	0010728
Is cancer (heuristic)	no

Also known as: fatal congenital hypertrophic cardiomyopathy due to glycogenosis · fatal congenital hypertrophic cardiomyopathy due to GSD · glycogen storage disease caused by mutation in PRKAG2 · phosphorylase kinase deficiency of heart · PRKAG2 glycogen storage disease

Data availability: 930 ClinVar variants · 1 GenCC gene-disease record.

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 › lethal congenital glycogen storage disease of heart

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, 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

600 retrieved; paginated sample, class counts are floors:

263 likely benign, 239 uncertain significance, 68 conflicting classifications of pathogenicity, 13 benign/likely benign, 9 benign, 5 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1452050	NM_016203.4(PRKAG2):c.1007T>C (p.Val336Ala)	PRKAG2	Pathogenic	criteria provided, single submitter
183142	NM_016203.4(PRKAG2):c.1151G>C (p.Arg384Thr)	PRKAG2	Pathogenic	no assertion criteria provided
2136632	NM_016203.4(PRKAG2):c.1453A>G (p.Lys485Glu)	PRKAG2	Pathogenic	criteria provided, single submitter
2735109	NM_016203.4(PRKAG2):c.1516G>A (p.Glu506Lys)	PRKAG2	Pathogenic	criteria provided, single submitter
36698	NM_016203.4(PRKAG2):c.879C>A (p.Phe293Leu)	PRKAG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3720795	NM_016203.4(PRKAG2):c.997T>C (p.Ser333Pro)	PRKAG2	Pathogenic	criteria provided, single submitter
2030739	NM_016203.4(PRKAG2):c.1642T>G (p.Ser548Ala)	PRKAG2	Likely pathogenic	criteria provided, single submitter
241091	NM_016203.4(PRKAG2):c.1201C>G (p.His401Asp)	PRKAG2	Likely pathogenic	criteria provided, single submitter
378427	NM_016203.4(PRKAG2):c.685-3C>T	LOC129999660	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
378428	NM_016203.4(PRKAG2):c.750C>T (p.Asp250=)	LOC129999660	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
410720	NM_016203.4(PRKAG2):c.704T>G (p.Leu235Arg)	LOC129999660	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420238	NM_016203.4(PRKAG2):c.754+13dup	LOC129999660	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014587	NM_016203.4(PRKAG2):c.562G>C (p.Glu188Gln)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042396	NM_016203.4(PRKAG2):c.1535A>G (p.Asn512Ser)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051753	NM_016203.4(PRKAG2):c.83A>G (p.Gln28Arg)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1171847	NM_016203.4(PRKAG2):c.642G>C (p.Arg214Ser)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1187307	NM_016203.4(PRKAG2):c.246G>T (p.Gln82His)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1198481	NM_016203.4(PRKAG2):c.1006G>T (p.Val336Leu)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1284764	NM_016203.4(PRKAG2):c.253C>T (p.Pro85Ser)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1311028	NM_016203.4(PRKAG2):c.182G>A (p.Arg61Gln)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1329302	NM_016203.4(PRKAG2):c.820G>A (p.Val274Ile)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1378785	NM_016203.4(PRKAG2):c.1438-3C>A	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1423265	NM_016203.4(PRKAG2):c.635C>T (p.Pro212Leu)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1475811	NM_016203.4(PRKAG2):c.571A>G (p.Ile191Val)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1521123	NM_016203.4(PRKAG2):c.1050G>A (p.Arg350=)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1596140	NM_016203.4(PRKAG2):c.318C>T (p.Phe106=)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
164991	NM_016203.4(PRKAG2):c.521C>T (p.Thr174Met)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
164993	NM_016203.4(PRKAG2):c.467-10T>G	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167533	NM_016203.4(PRKAG2):c.1304A>G (p.Asn435Ser)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1752896	NM_016203.4(PRKAG2):c.632G>A (p.Ser211Asn)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
PRKAG2	Strong	Autosomal dominant	lethal congenital glycogen storage disease of heart	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKAG2	Orphanet:439854	Fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease
XRCC2	Orphanet:227535	Hereditary breast cancer
XRCC2	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
XRCC2	Orphanet:84	Fanconi anemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRKAG2	HGNC:9386	ENSG00000106617	Q9UGJ0	5’-AMP-activated protein kinase subunit gamma-2	gencc,clinvar
XRCC2	HGNC:12829	ENSG00000196584	O43543	DNA repair protein XRCC2	clinvar
CHPF2	HGNC:29270	ENSG00000033100	Q9P2E5	Chondroitin sulfate glucuronyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKAG2	5’-AMP-activated protein kinase subunit gamma-2	AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism.
XRCC2	DNA repair protein XRCC2	Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions.
CHPF2	Chondroitin sulfate glucuronyltransferase	Transfers glucuronic acid (GlcUA) from UDP-GlcUA to N-acetylgalactosamine residues on the non-reducing end of the elongating chondroitin polymer.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRKAG2	Other/Unknown	no		CBS_dom, CBS_dom_sf, AMPK_gamma/SDS23_families
XRCC2	Other/Unknown	no		Rad51_C, RecA_ATP-bd, P-loop_NTPase
CHPF2	Enzyme (other)	yes	2.4.1.226	Chond_GalNAc, CS_glycosyltransferase

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac atrium	1
cardiac muscle of right atrium	1
right atrium auricular region	1
buccal mucosa cell	1
lateral globus pallidus	1
tendon of biceps brachii	1
adenohypophysis	1
pituitary gland	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKAG2	258	ubiquitous	marker	right atrium auricular region, cardiac atrium, cardiac muscle of right atrium
XRCC2	283	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, lateral globus pallidus
CHPF2	141	ubiquitous	marker	stromal cell of endometrium, pituitary gland, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKAG2	3,212
XRCC2	1,314
CHPF2	995

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
XRCC2	O43543	16

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHPF2	Q9P2E5	84.86
PRKAG2	Q9UGJ0	67.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 43. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
AMPK inhibits chREBP transcriptional activation activity	1	475.8×	0.026	PRKAG2
Lipophagy	1	423.0×	0.026	PRKAG2
Activation of PPARGC1A (PGC-1alpha) by phosphorylation	1	380.7×	0.026	PRKAG2
Carnitine shuttle	1	253.8×	0.026	PRKAG2
CS-GAG biosynthesis	1	181.3×	0.026	CHPF2
Impaired BRCA2 binding to PALB2	1	152.3×	0.026	XRCC2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	141.0×	0.026	XRCC2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	141.0×	0.026	XRCC2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	141.0×	0.026	XRCC2
Energy dependent regulation of mTOR by LKB1-AMPK	1	131.3×	0.026	PRKAG2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	131.3×	0.026	XRCC2
Homologous DNA Pairing and Strand Exchange	1	126.9×	0.026	XRCC2
Activation of AMPK downstream of NMDARs	1	126.9×	0.026	PRKAG2
Resolution of D-loop Structures through Holliday Junction Intermediates	1	100.2×	0.028	XRCC2
Selective autophagy	1	92.8×	0.028	PRKAG2
Presynaptic phase of homologous DNA pairing and strand exchange	1	90.6×	0.028	XRCC2
MTOR signalling	1	88.5×	0.028	PRKAG2
Post NMDA receptor activation events	1	68.0×	0.033	PRKAG2
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	64.5×	0.033	PRKAG2
HDR through Homologous Recombination (HRR)	1	63.4×	0.033	XRCC2
Activation of NMDA receptors and postsynaptic events	1	61.4×	0.033	PRKAG2
Integration of energy metabolism	1	58.6×	0.033	PRKAG2
Mitochondrial biogenesis	1	56.0×	0.033	PRKAG2
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	51.4×	0.035	PRKAG2
Autophagy	1	49.4×	0.035	PRKAG2
Regulation of TP53 Activity	1	44.3×	0.035	PRKAG2
Fatty acid metabolism	1	43.8×	0.035	PRKAG2
TP53 Regulates Metabolic Genes	1	43.3×	0.035	PRKAG2
Regulation of TP53 Activity through Phosphorylation	1	39.2×	0.037	PRKAG2
Macroautophagy	1	38.5×	0.037	PRKAG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of carbon utilization	1	1872.4×	0.005	PRKAG2
regulation of fatty acid oxidation	1	1872.4×	0.005	PRKAG2
regulation of fibroblast apoptotic process	1	1872.4×	0.005	XRCC2
DNA strand invasion	1	1404.3×	0.005	XRCC2
regulation of D-glucose import across plasma membrane	1	702.2×	0.008	PRKAG2
regulation of fatty acid metabolic process	1	624.1×	0.008	PRKAG2
sterol biosynthetic process	1	561.7×	0.008	PRKAG2
regulation of glycolytic process	1	401.2×	0.009	PRKAG2
ATP biosynthetic process	1	330.4×	0.010	PRKAG2
response to X-ray	1	295.6×	0.010	XRCC2
positive regulation of gluconeogenesis	1	255.3×	0.011	PRKAG2
chondroitin sulfate proteoglycan biosynthetic process	1	208.1×	0.011	CHPF2
response to gamma radiation	1	193.7×	0.011	XRCC2
positive regulation of neurogenesis	1	193.7×	0.011	XRCC2
glycogen metabolic process	1	175.5×	0.011	PRKAG2
cellular response to nutrient levels	1	156.0×	0.012	PRKAG2
somitogenesis	1	124.8×	0.013	XRCC2
fatty acid biosynthetic process	1	117.0×	0.013	PRKAG2
centrosome cycle	1	112.3×	0.013	XRCC2
cellular response to glucose starvation	1	112.3×	0.013	PRKAG2
meiotic cell cycle	1	81.4×	0.017	XRCC2
neurogenesis	1	69.3×	0.020	XRCC2
double-strand break repair via homologous recombination	1	52.0×	0.025	XRCC2
multicellular organism growth	1	45.7×	0.027	XRCC2
mitotic cell cycle	1	44.6×	0.027	XRCC2
negative regulation of neuron apoptotic process	1	37.0×	0.031	XRCC2
regulation of cell cycle	1	24.9×	0.044	PRKAG2
in utero embryonic development	1	24.0×	0.044	XRCC2
DNA repair	1	21.3×	0.048	XRCC2
intracellular signal transduction	1	12.7×	0.077	PRKAG2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PRKAG2	ADENOSINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKAG2	19	4
XRCC2	0	0
CHPF2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE PHOSPHATE	4	PRKAG2
CAPIVASERTIB	4	PRKAG2
SUNITINIB	4	PRKAG2
MIDOSTAURIN	4	PRKAG2
CRENOLANIB	3	PRKAG2
DOVITINIB	3	PRKAG2
LESTAURTINIB	3	PRKAG2
SILMITASERTIB	2	PRKAG2
REFAMETINIB	2	PRKAG2
DANUSERTIB	2	PRKAG2
AT-9283	2	PRKAG2
UCN-01	2	PRKAG2
BMS-754807	2	PRKAG2
SGI-1776	1	PRKAG2
AZD-7762	1	PRKAG2
PF-03758309	1	PRKAG2
TAK-901	1	PRKAG2
PF-03814735	1	PRKAG2
GSK-690693	1	PRKAG2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKAG2	266	Binding:265, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CHPF2	2.4.1.226	N-acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PRKAG2	266

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

19 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)
ADENOSINE PHOSPHATE	4	PRKAG2
CAPIVASERTIB	4	PRKAG2
SUNITINIB	4	PRKAG2
MIDOSTAURIN	4	PRKAG2
CRENOLANIB	3	PRKAG2
DOVITINIB	3	PRKAG2
LESTAURTINIB	3	PRKAG2
SILMITASERTIB	2	PRKAG2
REFAMETINIB	2	PRKAG2
DANUSERTIB	2	PRKAG2
AT-9283	2	PRKAG2
UCN-01	2	PRKAG2
BMS-754807	2	PRKAG2
SGI-1776	1	PRKAG2
AZD-7762	1	PRKAG2
PF-03758309	1	PRKAG2
TAK-901	1	PRKAG2
PF-03814735	1	PRKAG2
GSK-690693	1	PRKAG2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKAG2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CHPF2
E	Difficult family or no structure, no drug	1	XRCC2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
XRCC2	0	—
CHPF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.