Cardiomyopathy, familial restrictive, 1

Summary

Cardiomyopathy, familial restrictive, 1 (MONDO:0007270) is a disease caused by TNNI3 (GenCC Strong), with 7 cohort genes.

At a glance

• Causal gene: TNNI3 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 69

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiomyopathy, familial restrictive, 1
Mondo ID	MONDO:0007270
MeSH	C566168
OMIM	115210
DOID	DOID:0111425
UMLS	C1861861
MedGen	396236
GARD	0018070
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial restrictive, 1 · cardiomyopathy, familial restrictive, type 1 · familial isolated restrictive cardiomyopathy caused by mutation in TNNI3 · RCM1 · TNNI3 familial isolated restrictive cardiomyopathy

Data availability: 69 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, 1

Related subtypes (9): Gaucher disease type I, glycogen storage disease II, idiopathic hypereosinophilic syndrome, cardiomyopathy, familial restrictive, 2, cardiomyopathy, familial restrictive, 3, 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

69 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 23 conflicting classifications of pathogenicity, 6 pathogenic, 5 benign/likely benign, 4 pathogenic/likely pathogenic, 4 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
12423	NM_000363.5(TNNI3):c.569A>G (p.Asp190Gly)	TNNI3	Pathogenic	no assertion criteria provided
12424	NM_000363.5(TNNI3):c.575G>A (p.Arg192His)	TNNI3	Pathogenic	reviewed by expert panel
12425	NM_000363.5(TNNI3):c.532A>G (p.Lys178Glu)	TNNI3	Pathogenic	criteria provided, multiple submitters, no conflicts
12426	NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp)	TNNI3	Pathogenic	criteria provided, multiple submitters, no conflicts
12428	NM_000363.5(TNNI3):c.431T>A (p.Leu144Gln)	TNNI3	Pathogenic	no assertion criteria provided
1686263	NM_000363.5(TNNI3):c.130T>G (p.Ser44Ala)	TNNI3	Pathogenic	criteria provided, single submitter
179285	NM_000363.5(TNNI3):c.508C>T (p.Arg170Trp)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
265829	NM_001289808.2(CRYAB):c.326A>G (p.Asp109Gly)	CRYAB	Likely pathogenic	criteria provided, single submitter
165510	NM_000363.5(TNNI3):c.574C>T (p.Arg192Cys)	TNNI3	Likely pathogenic	reviewed by expert panel
265828	NM_000363.5(TNNI3):c.379G>T (p.Asp127Tyr)	TNNI3	Likely pathogenic	no assertion criteria provided
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
12429	NM_000363.5(TNNI3):c.511G>A (p.Ala171Thr)	TNNI3	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
165517	NM_000363.5(TNNI3):c.508C>G (p.Arg170Gly)	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
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
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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 16 · 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
MYPN	Orphanet:154	Familial isolated dilated cardiomyopathy
MYPN	Orphanet:171439	Childhood-onset nemaline myopathy
MYPN	Orphanet:171881	Cap myopathy
MYPN	Orphanet:75249	Familial isolated restrictive cardiomyopathy
CRYAB	Orphanet:154	Familial isolated dilated cardiomyopathy
CRYAB	Orphanet:280553	Fatal infantile hypertonic myofibrillar myopathy
CRYAB	Orphanet:399058	Alpha-B crystallin-related late-onset myopathy
CRYAB	Orphanet:441452	Early-onset lamellar cataract
CRYAB	Orphanet:98991	Early-onset nuclear cataract
CRYAB	Orphanet:98993	Early-onset posterior polar cataract
DNAAF3	Orphanet:244	Primary ciliary dyskinesia
FLNC	Orphanet:171445	Muscle filaminopathy
FLNC	Orphanet:63273	FLNC-related handgrip and calf weakness-distal myopathy
FLNC	Orphanet:75249	Familial isolated restrictive cardiomyopathy

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNI3	HGNC:11947	ENSG00000129991	P19429	Troponin I, cardiac muscle	gencc,clinvar
MYPN	HGNC:23246	ENSG00000138347	Q86TC9	Myopalladin	clinvar
CRYAB	HGNC:2389	ENSG00000109846	P02511	Alpha-crystallin B chain	clinvar
DNAAF3	HGNC:30492	ENSG00000167646	Q8N9W5	Dynein axonemal assembly factor 3	clinvar
FLNC	HGNC:3756	ENSG00000128591	Q14315	Filamin-C	clinvar
DNAAF3-AS1	HGNC:55292	ENSG00000267577		DNAAF3 antisense RNA 1	clinvar
MYL3	HGNC:7584	ENSG00000160808	P08590	Myosin light chain 3	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.
MYPN	Myopalladin	Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
CRYAB	Alpha-crystallin B chain	May contribute to the transparency and refractive index of the lens.
DNAAF3	Dynein axonemal assembly factor 3	Required for the assembly of axonemal inner and outer dynein arms.
FLNC	Filamin-C	Muscle-specific filamin, which plays a central role in sarcomere assembly and organization.
MYL3	Myosin light chain 3	Regulatory light chain of myosin.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.29

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
Antibody/Immunoglobulin	2	8.3×	0.044
Other/Unknown	5	1.3×	0.332

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNNI3	Other/Unknown	no		Troponin, Troponin-I_N, Troponin_sf
MYPN	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
CRYAB	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N
DNAAF3	Other/Unknown	no		DUF4470, DNAAF3_C, DNAAF3
FLNC	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
DNAAF3-AS1	Other/Unknown	no
MYL3	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, CALM/Myosin/TropC-like

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	4
hindlimb stylopod muscle	3
left ventricle myocardium	2
gastrocnemius	2
right atrium auricular region	1
vastus lateralis	1
cardiac ventricle	1
middle frontal gyrus	1
right testis	1
right uterine tube	1
tibialis anterior	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1
heart right ventricle	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
MYPN	116	broad	marker	hindlimb stylopod muscle, gastrocnemius, vastus lateralis
CRYAB	289	ubiquitous	marker	middle frontal gyrus, left ventricle myocardium, cardiac ventricle
DNAAF3	158	broad	marker	apex of heart, right uterine tube, right testis
FLNC	255	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, tibialis anterior
DNAAF3-AS1	110		yes	sperm, apex of heart, male germ line stem cell (sensu Vertebrata) in testis
MYL3	198	broad	marker	apex of heart, heart right ventricle, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRYAB	3,368
FLNC	3,174
MYL3	2,255
TNNI3	1,836
MYPN	1,764
DNAAF3	794
DNAAF3-AS1	0

Intra-cohort edges

A	B	Sources
CRYAB	FLNC	string_interaction
MYL3	TNNI3	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNNI3	P19429	39
CRYAB	P02511	21
FLNC	Q14315	14
MYL3	P08590	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAAF3	Q8N9W5	81.06
MYPN	Q86TC9	52.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 7 evidence-associated genes (4 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 4 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	2	154.3×	3e-04	TNNI3, MYL3
Cell-extracellular matrix interactions	1	167.9×	0.015	FLNC
HSF1-dependent transactivation	1	79.3×	0.021	CRYAB
Ion homeostasis	1	51.0×	0.024	TNNI3
Muscle contraction	1	19.3×	0.051	MYL3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ventricular cardiac muscle tissue morphogenesis	2	234.1×	0.002	TNNI3, MYL3
cardiac muscle contraction	2	133.8×	0.002	TNNI3, MYL3
sarcomere organization	2	127.7×	0.002	MYPN, FLNC
microtubule polymerization or depolymerization	1	2808.7×	0.004	CRYAB
muscle contraction	2	69.3×	0.004	CRYAB, MYL3
regulation of systemic arterial blood pressure by ischemic conditions	1	1404.3×	0.007	TNNI3
negative regulation of intracellular transport	1	936.2×	0.008	CRYAB
regulation of programmed cell death	1	468.1×	0.013	CRYAB
apoptotic process involved in morphogenesis	1	468.1×	0.013	CRYAB
heart development	2	26.2×	0.013	TNNI3, DNAAF3
regulation of striated muscle contraction	1	351.1×	0.014	MYL3
tubulin complex assembly	1	280.9×	0.015	CRYAB
negative regulation of ATP-dependent activity	1	280.9×	0.015	TNNI3
regulation of cardiac muscle contraction by calcium ion signaling	1	216.1×	0.016	TNNI3
negative regulation of amyloid fibril formation	1	216.1×	0.016	CRYAB
regulation of smooth muscle contraction	1	200.6×	0.016	TNNI3
muscle filament sliding	1	175.5×	0.016	TNNI3
axonemal dynein complex assembly	1	175.5×	0.016	DNAAF3
dendrite self-avoidance	1	175.5×	0.016	MYPN
regulation of the force of heart contraction	1	165.2×	0.017	MYL3
negative regulation of reactive oxygen species metabolic process	1	156.0×	0.017	CRYAB
cerebrospinal fluid circulation	1	147.8×	0.017	DNAAF3
heart contraction	1	127.7×	0.018	TNNI3
seminiferous tubule development	1	127.7×	0.018	DNAAF3
stress-activated MAPK cascade	1	117.0×	0.019	CRYAB
protein refolding	1	104.0×	0.020	CRYAB
cellular response to gamma radiation	1	100.3×	0.020	CRYAB
motile cilium assembly	1	96.8×	0.020	DNAAF3
skeletal muscle contraction	1	85.1×	0.022	TNNI3
response to hydrogen peroxide	1	78.0×	0.023	CRYAB

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 3 of 7 evidence-associated genes (43%) 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
MYPN	0	0
CRYAB	0	0
DNAAF3	0	0
FLNC	0	0
DNAAF3-AS1	0	0
MYL3	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
CRYAB	13	Binding:13
TNNI3	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	1	FLNC
D	Druggable family + AlphaFold only, no drug	1	MYPN
E	Difficult family or no structure, no drug	5	TNNI3, CRYAB, DNAAF3, DNAAF3-AS1, MYL3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNNI3	2	—
MYPN	0	—
CRYAB	13	—
DNAAF3	0	—
FLNC	0	—
DNAAF3-AS1	0	—
MYL3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.