Intrinsic cardiomyopathy

Summary

Intrinsic cardiomyopathy (MONDO:0000591) is a disease (an umbrella term covering 6 Mondo subtypes) caused by PLN (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: PLN (GenCC Strong)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 9
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intrinsic cardiomyopathy
Mondo ID	MONDO:0000591
DOID	DOID:0060036
GARD	0022809
Is cancer (heuristic)	no

Also known as: intrinsic cardiomyopathy · primary cardiomyopathy

Data availability: 9 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy

Related subtypes (11): Keshan disease, extrinsic cardiomyopathy, idiopathic cardiomyopathy, familial cardiomyopathy, non-compaction cardiomyopathy, Chagas cardiomyopathy, Uhl anomaly, Tako-tsubo cardiomyopathy, cardiomyopathy due to anthracyclines, doxorubicin induced cardiomyopathy, autoimmune cardiomyopathy

Subtypes (6): myocarditis, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction

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

9 retrieved; paginated sample, class counts are floors:

4 conflicting classifications of pathogenicity, 3 likely pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13637	NM_002667.5(PLN):c.116T>G (p.Leu39Ter)	PLN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326967	NM_001103.4(ACTN2):c.698-2A>G	ACTN2	Likely pathogenic	criteria provided, single submitter
3068664	NM_001103.4(ACTN2):c.239C>G (p.Ser80Ter)	ACTN2	Likely pathogenic	criteria provided, single submitter
4528932	NM_001103.4(ACTN2):c.448+1115_615+666del	ACTN2	Likely pathogenic	criteria provided, single submitter
162745	NM_001103.4(ACTN2):c.2555G>A (p.Arg852Gln)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18313	NM_001103.4(ACTN2):c.26A>G (p.Gln9Arg)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43922	NM_001103.4(ACTN2):c.2003C>G (p.Thr668Arg)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
645022	NM_001103.4(ACTN2):c.1337C>T (p.Ala446Val)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1326968	NM_001103.4(ACTN2):c.2575G>A (p.Ala859Thr)	ACTN2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 5 · 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
PLN	Definitive	Autosomal dominant	dilated cardiomyopathy 1P	9
ACTN2	Moderate	Autosomal dominant	dilated cardiomyopathy 1AA	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTN2	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTN2	Orphanet:708129	Autosomal recessive ACTN2-related distal myopathy
ACTN2	Orphanet:708133	Autosomal dominant ACTN2-related distal myopathy
PLN	Orphanet:154	Familial isolated dilated cardiomyopathy
PLN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTN2	HGNC:164	ENSG00000077522	P35609	Alpha-actinin-2	gencc,clinvar
PLN	HGNC:9080	ENSG00000198523	P26678	Phospholamban	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTN2	Alpha-actinin-2	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
PLN	Phospholamban	Reversibly inhibits the activity of ATP2A2/SERCA2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTN2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
PLN	Other/Unknown	no		PLB

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
heart right ventricle	1
left ventricle myocardium	1
myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTN2	226	broad	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle
PLN	243	broad	marker	heart right ventricle, myocardium, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTN2	2,781
PLN	1,080

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTN2	P35609	16
PLN	P26678	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	439.2×	0.017	ACTN2
Ras activation upon Ca2+ influx through NMDA receptor	1	285.5×	0.017	ACTN2
Unblocking of NMDA receptors, glutamate binding and activation	1	271.9×	0.017	ACTN2
Negative regulation of NMDA receptor-mediated neuronal transmission	1	271.9×	0.017	ACTN2
Nephrin family interactions	1	237.9×	0.017	ACTN2
Long-term potentiation	1	237.9×	0.017	ACTN2
Striated Muscle Contraction	1	154.3×	0.022	ACTN2
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.022	ACTN2
Ion transport by P-type ATPases	1	103.8×	0.022	PLN
Post NMDA receptor activation events	1	102.0×	0.022	ACTN2
Ion homeostasis	1	102.0×	0.022	PLN
Activation of NMDA receptors and postsynaptic events	1	92.1×	0.023	ACTN2
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.024	ACTN2
Cell-Cell communication	1	68.8×	0.025	ACTN2
MAPK1/MAPK3 signaling	1	65.6×	0.025	ACTN2
Platelet activation, signaling and aggregation	1	52.9×	0.028	ACTN2
MAPK family signaling cascades	1	51.4×	0.028	ACTN2
Neurotransmitter receptors and postsynaptic signal transmission	1	50.1×	0.028	ACTN2
Platelet degranulation	1	43.9×	0.030	ACTN2
Muscle contraction	1	38.6×	0.031	ACTN2
Transmission across Chemical Synapses	1	38.1×	0.031	ACTN2
RAF/MAP kinase cascade	1	30.5×	0.037	ACTN2
Neuronal System	1	22.1×	0.049	ACTN2
Hemostasis	1	18.0×	0.057	ACTN2
Signal Transduction	1	5.1×	0.187	ACTN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
circadian sleep/wake cycle, sleep	1	8426.0×	0.002	PLN
actin filament uncapping	1	8426.0×	0.002	ACTN2
adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process	1	8426.0×	0.002	PLN
regulation of the force of heart contraction by cardiac conduction	1	4213.0×	0.002	PLN
regulation of relaxation of cardiac muscle	1	4213.0×	0.002	PLN
phospholipase C-activating angiotensin-activated signaling pathway	1	2808.7×	0.002	ACTN2
regulation of ATPase-coupled calcium transmembrane transporter activity	1	2808.7×	0.002	PLN
negative regulation of ATPase-coupled calcium transmembrane transporter activity	1	2808.7×	0.002	PLN
microspike assembly	1	2106.5×	0.002	ACTN2
negative regulation of calcium ion import into sarcoplasmic reticulum	1	2106.5×	0.002	PLN
positive regulation of endocytic recycling	1	1404.3×	0.003	ACTN2
regulation of cardiac muscle cell membrane potential	1	1203.7×	0.003	PLN
negative regulation of calcium ion import	1	1203.7×	0.003	PLN
positive regulation of potassium ion transport	1	1053.2×	0.003	ACTN2
negative regulation of potassium ion transport	1	936.2×	0.003	ACTN2
negative regulation of calcium ion transport	1	842.6×	0.003	PLN
negative regulation of heart rate	1	648.1×	0.004	PLN
relaxation of cardiac muscle	1	648.1×	0.004	PLN
negative regulation of protein localization to cell surface	1	648.1×	0.004	ACTN2
regulation of cardiac muscle cell contraction	1	561.7×	0.004	PLN
locomotor rhythm	1	526.6×	0.004	PLN
regulation of the force of heart contraction	1	495.6×	0.004	PLN
muscle cell development	1	468.1×	0.004	ACTN2
cardiac muscle tissue development	1	443.5×	0.004	PLN
regulation of calcium ion transport	1	401.2×	0.005	PLN
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	337.0×	0.005	PLN
muscle cell cellular homeostasis	1	324.1×	0.005	PLN
response to zinc ion	1	312.1×	0.005	PLN
cardiac muscle cell development	1	312.1×	0.005	ACTN2
focal adhesion assembly	1	263.3×	0.006	ACTN2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACTN2	0	0
PLN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ACTN2, PLN

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)
ACTN2	0	—
PLN	0	—

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
NCT03572569	Not specified	UNKNOWN	Risk Stratification in Children and Adolescents With Primary Cardiomyopathy