Cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction

Summary

Cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction (MONDO:0800347) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction
Mondo ID	MONDO:0800347
UMLS	C4225649
MedGen	897129
GARD	0026512
Is cancer (heuristic)	no

Also known as: CMH23

Data availability: 5 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › hypertrophic cardiomyopathy › familial hypertrophic cardiomyopathy › cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction

Related subtypes (39): hypertrophic cardiomyopathy 2, hypertrophic cardiomyopathy 3, hypertrophic cardiomyopathy 4, Beckwith-Wiedemann syndrome, myotonic dystrophy type 1, hypertrophic cardiomyopathy 1, very long chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, 46,XY complete gonadal dysgenesis, hypertrophic cardiomyopathy 6, dilated cardiomyopathy 1C, hypertrophic cardiomyopathy 25, hypertrophic cardiomyopathy 8, hypertrophic cardiomyopathy 10, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, cardiomyopathy-hypotonia-lactic acidosis syndrome, hypertrophic cardiomyopathy 11, hypertrophic cardiomyopathy 12, hypertrophic cardiomyopathy 13, hypertrophic cardiomyopathy 14, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy 7, hypertrophic cardiomyopathy 9, hypertrophic cardiomyopathy 16, hypertrophic cardiomyopathy 17, hypertrophic cardiomyopathy 18, hypertrophic cardiomyopathy 19, hypertrophic cardiomyopathy 20, hypertrophic cardiomyopathy 21, dilated cardiomyopathy 1KK, hypertrophic cardiomyopathy 26, Noonan syndrome and Noonan-related syndrome, long chain acyl-CoA dehydrogenase deficiency, cardiomyopathy, familial hypertrophic, 28, cardiomyopathy, familial hypertrophic 27, cardiomyopathy, familial restrictive, 5, cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, cardiomyopathy, familial hypertrophic, 30, atrial, cardiomyopathy, familial hypertrophic, 31

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

5 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 pathogenic/likely pathogenic, 1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
162727	NM_001103.4(ACTN2):c.355G>A (p.Ala119Thr)	ACTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189516	NM_001103.4(ACTN2):c.2276G>C (p.Arg759Thr)	ACTN2	Pathogenic	no assertion criteria provided
189517	NM_001103.4(ACTN2):c.1883A>G (p.Glu628Gly)	ACTN2	Pathogenic	no assertion criteria provided
43911	NM_001103.4(ACTN2):c.1484C>T (p.Thr495Met)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
189514	NM_001103.4(ACTN2):c.332G>T (p.Gly111Val)	ACTN2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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

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
ACTN2	HGNC:164	ENSG00000077522	P35609	Alpha-actinin-2	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

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

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
hindlimb stylopod muscle	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTN2	2,781

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTN2	P35609	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. 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
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	878.5×	0.008	ACTN2
Ras activation upon Ca2+ influx through NMDA receptor	1	571.0×	0.008	ACTN2
Unblocking of NMDA receptors, glutamate binding and activation	1	543.8×	0.008	ACTN2
Negative regulation of NMDA receptor-mediated neuronal transmission	1	543.8×	0.008	ACTN2
Nephrin family interactions	1	475.8×	0.008	ACTN2
Long-term potentiation	1	475.8×	0.008	ACTN2
Striated Muscle Contraction	1	308.6×	0.011	ACTN2
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.011	ACTN2
Post NMDA receptor activation events	1	203.9×	0.012	ACTN2
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.012	ACTN2
Response to elevated platelet cytosolic Ca2+	1	163.1×	0.013	ACTN2
Cell-Cell communication	1	137.6×	0.013	ACTN2
MAPK1/MAPK3 signaling	1	131.3×	0.013	ACTN2
Platelet activation, signaling and aggregation	1	105.7×	0.014	ACTN2
MAPK family signaling cascades	1	102.9×	0.014	ACTN2
Neurotransmitter receptors and postsynaptic signal transmission	1	100.2×	0.014	ACTN2
Platelet degranulation	1	87.8×	0.015	ACTN2
Muscle contraction	1	77.2×	0.016	ACTN2
Transmission across Chemical Synapses	1	76.1×	0.016	ACTN2
RAF/MAP kinase cascade	1	61.1×	0.019	ACTN2
Neuronal System	1	44.3×	0.025	ACTN2
Hemostasis	1	36.0×	0.029	ACTN2
Signal Transduction	1	10.2×	0.098	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
actin filament uncapping	1	16852.0×	9e-04	ACTN2
phospholipase C-activating angiotensin-activated signaling pathway	1	5617.3×	0.001	ACTN2
microspike assembly	1	4213.0×	0.001	ACTN2
positive regulation of endocytic recycling	1	2808.7×	0.001	ACTN2
positive regulation of potassium ion transport	1	2106.5×	0.001	ACTN2
negative regulation of potassium ion transport	1	1872.4×	0.001	ACTN2
negative regulation of protein localization to cell surface	1	1296.3×	0.002	ACTN2
muscle cell development	1	936.2×	0.002	ACTN2
cardiac muscle cell development	1	624.1×	0.003	ACTN2
focal adhesion assembly	1	526.6×	0.003	ACTN2
sarcomere organization	1	383.0×	0.004	ACTN2
regulation of membrane potential	1	230.8×	0.006	ACTN2
protein localization to plasma membrane	1	108.7×	0.011	ACTN2
regulation of apoptotic process	1	83.4×	0.013	ACTN2
actin cytoskeleton organization	1	79.1×	0.013	ACTN2
cell adhesion	1	37.5×	0.027	ACTN2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ACTN2

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)
ACTN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.