Cardiomyopathy, familial restrictive, 3

Summary

Cardiomyopathy, familial restrictive, 3 (MONDO:0012900) is a disease caused by TNNT2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TNNT2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 764

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiomyopathy, familial restrictive, 3
Mondo ID	MONDO:0012900
MeSH	C567316
OMIM	612422
DOID	DOID:0111427
UMLS	C2676271
MedGen	382807
GARD	0018072
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial restrictive, 3 · cardiomyopathy, familial restrictive, type 3 · familial isolated restrictive cardiomyopathy caused by mutation in TNNT2 · RCM3 · TNNT2 familial isolated restrictive cardiomyopathy

Data availability: 764 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › restrictive cardiomyopathy › familial restrictive cardiomyopathy › cardiomyopathy, familial restrictive, 3

Related subtypes (9): cardiomyopathy, familial restrictive, 1, Gaucher disease type I, glycogen storage disease II, idiopathic hypereosinophilic syndrome, cardiomyopathy, familial restrictive, 2, dilated cardiomyopathy 1KK, atrial standstill, ATTRV122I amyloidosis, cardiomyopathy, familial restrictive, 6

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:

251 uncertain significance, 207 likely benign, 75 conflicting classifications of pathogenicity, 22 benign/likely benign, 19 pathogenic/likely pathogenic, 12 likely pathogenic, 8 benign, 6 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12408	NM_001276345.2(TNNT2):c.266T>A (p.Ile89Asn)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
12409	NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12412	NM_001276345.2(TNNT2):c.358T>A (p.Phe120Ile)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
12414	NM_001276345.2(TNNT2):c.451C>T (p.Arg151Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12415	NM_001276345.2(TNNT2):c.421C>T (p.Arg141Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165533	NM_001276345.2(TNNT2):c.851+1G>T	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165549	NM_001276345.2(TNNT2):c.310C>T (p.Arg104Cys)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177634	NM_001276345.2(TNNT2):c.566C>T (p.Ser189Phe)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177644	NM_001276345.2(TNNT2):c.274G>A (p.Gly92Arg)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177683	NM_001276345.2(TNNT2):c.316_318del (p.Glu106del)	TNNT2	Pathogenic/Likely pathogenic	no assertion criteria provided
177807	NM_001276345.2(TNNT2):c.360T>G (p.Phe120Leu)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
181636	NM_001276345.2(TNNT2):c.891G>A (p.Trp297Ter)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
181649	NM_001276345.2(TNNT2):c.851+1G>C	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2100789	NM_001276345.2(TNNT2):c.321G>C (p.Lys107Asn)	TNNT2	Pathogenic	criteria provided, single submitter
228409	NM_001276345.2(TNNT2):c.547C>T (p.Arg183Trp)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
3753583	NM_001276345.2(TNNT2):c.291T>G (p.Phe97Leu)	TNNT2	Pathogenic	criteria provided, single submitter
43626	NM_001276345.2(TNNT2):c.287A>C (p.Asp96Ala)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43627	NM_001276345.2(TNNT2):c.304C>T (p.Arg102Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43629	NM_001276345.2(TNNT2):c.311G>T (p.Arg104Leu)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43636	NM_001276345.2(TNNT2):c.418C>T (p.Arg140Cys)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43637	NM_001276345.2(TNNT2):c.422G>A (p.Arg141Gln)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
43639	NM_001276345.2(TNNT2):c.430C>G (p.Arg144Gly)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43648	NM_001276345.2(TNNT2):c.508GAG[3] (p.Glu173del)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43649	NM_001276345.2(TNNT2):c.548G>A (p.Arg183Gln)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43659	NM_001276345.2(TNNT2):c.650AGA[3] (p.Lys220del)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1435754	NM_001276345.2(TNNT2):c.283G>A (p.Val95Met)	TNNT2	Likely pathogenic	criteria provided, single submitter
1699339	NM_001276345.2(TNNT2):c.299T>A (p.Ile100Asn)	TNNT2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
177636	NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter)	TNNT2	Likely pathogenic	reviewed by expert panel
2115456	NM_001276345.2(TNNT2):c.445C>G (p.Arg149Gly)	TNNT2	Likely pathogenic	criteria provided, single submitter
2202921	NM_001276345.2(TNNT2):c.290T>A (p.Phe97Tyr)	TNNT2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
TNNT2	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 2	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:75249	Familial isolated restrictive cardiomyopathy

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
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNNT2	Troponin T, cardiac muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.

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)
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf

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
apex of heart	1
cardiac atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNNT2	1,944

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNNT2	P45379	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Striated Muscle Contraction	1	308.6×	0.003	TNNT2

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
regulation of muscle contraction	1	1685.2×	0.002	TNNT2
negative regulation of ATP-dependent activity	1	1685.2×	0.002	TNNT2
positive regulation of ATP-dependent activity	1	1404.3×	0.002	TNNT2
muscle filament sliding	1	1053.2×	0.002	TNNT2
ventricular cardiac muscle tissue morphogenesis	1	702.2×	0.003	TNNT2
regulation of heart contraction	1	495.6×	0.003	TNNT2
cardiac muscle contraction	1	401.2×	0.003	TNNT2
sarcomere organization	1	383.0×	0.003	TNNT2
response to calcium ion	1	318.0×	0.003	TNNT2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNNT2	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
TNNT2	2	Binding:2

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	TNNT2

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)
TNNT2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.