dilated cardiomyopathy 2A

Summary

dilated cardiomyopathy 2A (MONDO:0012746) is a disease caused by TNNI3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: TNNI3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 59

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dilated cardiomyopathy 2A
Mondo ID	MONDO:0012746
OMIM	611880
DOID	DOID:0110460
UMLS	C2678474
MedGen	437214
GARD	0015532
Is cancer (heuristic)	no

Also known as: cardiomyopathy, dilated, 2A · cardiomyopathy, dilated, type 2A · CMD2A · dilated cardiomyopathy type 2A

Data availability: 59 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › dilated cardiomyopathy › familial dilated cardiomyopathy › familial isolated dilated cardiomyopathy › dilated cardiomyopathy 2A

Related subtypes (44): dilated cardiomyopathy 1A, dilated cardiomyopathy 3B, dilated cardiomyopathy 1B, dilated cardiomyopathy 1E, dilated cardiomyopathy 1C, dilated cardiomyopathy 1D, dilated cardiomyopathy 1G, dilated cardiomyopathy 1H, dilated cardiomyopathy 1I, dilated cardiomyopathy 1K, dilated cardiomyopathy 1L, dilated cardiomyopathy 1M, dilated cardiomyopathy 1O, dilated cardiomyopathy 1P, dilated cardiomyopathy 1Q, dilated cardiomyopathy 1W, dilated cardiomyopathy 1X, dilated cardiomyopathy 1Y, dilated cardiomyopathy 1Z, dilated cardiomyopathy 1AA, dilated cardiomyopathy 1BB, dilated cardiomyopathy 1CC, dilated cardiomyopathy 1DD, dilated cardiomyopathy 1EE, dilated cardiomyopathy 1FF, dilated cardiomyopathy 1R, dilated cardiomyopathy 1S, dilated cardiomyopathy 1GG, dilated cardiomyopathy 1U, dilated cardiomyopathy 1V, dilated cardiomyopathy 1HH, dilated cardiomyopathy 2B, dilated cardiomyopathy 1II, dilated cardiomyopathy 1JJ, dilated cardiomyopathy 1KK, left ventricular noncompaction 8, left ventricular noncompaction 10, dilated cardiomyopathy 1NN, cardiomyopathy, dilated, 2D, cardiomyopathy, dilated, 2E, cardiomyopathy, dilated, 2F, cardiomyopathy, dilated, 2G, cardiomyopathy, dilated, 2c, cardiomyopathy, dilated, 2H

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

59 retrieved; paginated sample, class counts are floors:

23 conflicting classifications of pathogenicity, 19 uncertain significance, 5 benign/likely benign, 3 pathogenic/likely pathogenic, 3 pathogenic, 3 likely pathogenic, 2 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12422	NM_000363.5(TNNI3):c.586G>A (p.Asp196Asn)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12424	NM_000363.5(TNNI3):c.575G>A (p.Arg192His)	TNNI3	Pathogenic	reviewed by expert panel
12426	NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp)	TNNI3	Pathogenic	criteria provided, multiple submitters, no conflicts
3775215	NM_000363.5(TNNI3):c.295C>T (p.Gln99Ter)	TNNI3	Pathogenic	criteria provided, single submitter
43381	NM_000363.5(TNNI3):c.422G>A (p.Arg141Gln)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43384	NM_000363.5(TNNI3):c.434G>A (p.Arg145Gln)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165510	NM_000363.5(TNNI3):c.574C>T (p.Arg192Cys)	TNNI3	Likely pathogenic	reviewed by expert panel
4086222	NM_000363.5(TNNI3):c.456T>A (p.Asp152Glu)	TNNI3	Likely pathogenic	criteria provided, single submitter
43389	NM_000363.5(TNNI3):c.485G>A (p.Arg162Gln)	TNNI3	Likely pathogenic	reviewed by expert panel
894093	NM_001256715.2(DNAAF3):c.990C>T (p.Thr330=)	DNAAF3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
257685	NM_001256715.2(DNAAF3):c.1248G>A (p.Val416=)	DNAAF3-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137685	NM_000363.5(TNNI3):c.139T>C (p.Leu47=)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165519	NM_000363.5(TNNI3):c.372+7C>T	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179447	NM_000363.5(TNNI3):c.204del (p.Arg69fs)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
181575	NM_000363.5(TNNI3):c.292C>T (p.Arg98Ter)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188666	NM_000363.5(TNNI3):c.-98C>A	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188667	NM_000363.5(TNNI3):c.-47C>T	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188677	NM_000363.5(TNNI3):c.*35C>T	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
229330	NM_000363.5(TNNI3):c.109-15A>G	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3234113	NM_000363.5(TNNI3):c.184G>T (p.Glu62Ter)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330199	NM_000363.5(TNNI3):c.283-9C>T	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36881	NM_000363.5(TNNI3):c.373-10=	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
378932	NM_000363.5(TNNI3):c.108+2T>G	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
419596	NM_000363.5(TNNI3):c.114dup (p.Ser39fs)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43363	NM_000363.5(TNNI3):c.151-6C>G	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43366	NM_000363.5(TNNI3):c.204G>T (p.Arg68=)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43367	NM_000363.5(TNNI3):c.235C>T (p.Arg79Cys)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43372	NM_000363.5(TNNI3):c.273G>A (p.Ala91=)	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43377	NM_000363.5(TNNI3):c.373-15C>G	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43378	NM_000363.5(TNNI3):c.373-4C>G	TNNI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
TNNI3	Definitive	Autosomal recessive	dilated cardiomyopathy 2A	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNI3	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNI3	Orphanet:75249	Familial isolated restrictive cardiomyopathy
DNAAF3	Orphanet:244	Primary ciliary dyskinesia

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNI3	HGNC:11947	ENSG00000129991	P19429	Troponin I, cardiac muscle	gencc,clinvar
DNAAF3	HGNC:30492	ENSG00000167646	Q8N9W5	Dynein axonemal assembly factor 3	clinvar
DNAAF3-AS1	HGNC:55292	ENSG00000267577		DNAAF3 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNI3	Troponin I, cardiac muscle	Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
DNAAF3	Dynein axonemal assembly factor 3	Required for the assembly of axonemal inner and outer dynein arms.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNI3	Other/Unknown	no		Troponin, Troponin-I_N, Troponin_sf
DNAAF3	Other/Unknown	no		DUF4470, DNAAF3_C, DNAAF3
DNAAF3-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	3
left ventricle myocardium	1
right atrium auricular region	1
right testis	1
right uterine tube	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNI3	169	broad	marker	apex of heart, left ventricle myocardium, right atrium auricular region
DNAAF3	158	broad	marker	apex of heart, right uterine tube, right testis
DNAAF3-AS1	110		yes	sperm, apex of heart, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNNI3	1,836
DNAAF3	794
DNAAF3-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNNI3	P19429	39

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAAF3	Q8N9W5	81.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Striated Muscle Contraction	1	308.6×	0.005	TNNI3
Ion homeostasis	1	203.9×	0.005	TNNI3

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
regulation of systemic arterial blood pressure by ischemic conditions	1	4213.0×	0.003	TNNI3
heart development	2	78.8×	0.003	TNNI3, DNAAF3
negative regulation of ATP-dependent activity	1	842.6×	0.006	TNNI3
regulation of cardiac muscle contraction by calcium ion signaling	1	648.1×	0.006	TNNI3
regulation of smooth muscle contraction	1	601.9×	0.006	TNNI3
muscle filament sliding	1	526.6×	0.006	TNNI3
axonemal dynein complex assembly	1	526.6×	0.006	DNAAF3
cerebrospinal fluid circulation	1	443.5×	0.006	DNAAF3
heart contraction	1	383.0×	0.006	TNNI3
seminiferous tubule development	1	383.0×	0.006	DNAAF3
ventricular cardiac muscle tissue morphogenesis	1	351.1×	0.006	TNNI3
motile cilium assembly	1	290.6×	0.007	DNAAF3
skeletal muscle contraction	1	255.3×	0.007	TNNI3
determination of adult lifespan	1	216.1×	0.008	DNAAF3
cardiac muscle contraction	1	200.6×	0.008	TNNI3
vasculogenesis	1	127.7×	0.011	TNNI3
determination of left/right symmetry	1	127.7×	0.011	DNAAF3
lung development	1	99.1×	0.013	DNAAF3
cell morphogenesis	1	78.8×	0.015	DNAAF3
intracellular calcium ion homeostasis	1	72.6×	0.016	TNNI3
multicellular organism growth	1	68.5×	0.016	DNAAF3
brain development	1	39.8×	0.026	DNAAF3
spermatogenesis	1	17.6×	0.056	DNAAF3

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNNI3	0	0
DNAAF3	0	0
DNAAF3-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TNNI3	2	Binding:2

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	3	TNNI3, DNAAF3, DNAAF3-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNNI3	2	—
DNAAF3	0	—
DNAAF3-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.