Myofibrillar myopathy

Summary

Myofibrillar myopathy (MONDO:0018943) is a disease (an umbrella term covering 13 Mondo subtypes) caused by variants in BAG3 and FLNC, with 7 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal genes: BAG3 (GenCC Definitive), FLNC (GenCC Strong)
• Umbrella term: 13 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 12
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myofibrillar myopathy
Mondo ID	MONDO:0018943
MeSH	C580316
OMIM	601419
Orphanet	593
DOID	DOID:0080307
ICD-11	125656853
NCIT	C83009
SNOMED CT	699269005
UMLS	C2678065
MedGen	395532
GARD	0010529
Is cancer (heuristic)	no

Also known as: Alpha Beta crystallinopathy (type) · desmin related myopathy (former name) · desmin storage myopathy (former name) · Desminopathy (type) · filaminopathy (type) · myofibrillar myopathies · myofibrillar myopathy · myofibrillar myopathy (disease) · myotilinopathy (type) · Protein surplus myopathy (former name) · Zaspopathy (type)

Data availability: 12 ClinVar variants · 3 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 13 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › myofibrillar myopathy

Related subtypes (5): autosomal dominant centronuclear myopathy, inborn mitochondrial myopathy, congenital fiber-type disproportion myopathy, nemaline myopathy, autosomal dominant nebulin-related myopathy

Subtypes (13): central core myopathy, myofibrillar myopathy 1, myofibrillar myopathy 3, myofibrillar myopathy 4, myofibrillar myopathy 5, myofibrillar myopathy 6, fatal infantile hypertonic myofibrillar myopathy, myofibrillar myopathy 7, myofibrillar myopathy 8, myofibrillar myopathy 11, myofibrillar myopathy 10, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, myopathy, myofibrillar, 13, with rimmed vacuoles

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

12 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
66390	NM_001927.4(DES):c.1069G>C (p.Ala357Pro)	DES	Pathogenic	criteria provided, single submitter
66400	NM_001927.4(DES):c.1346A>C (p.Lys449Thr)	DES	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694402	NM_001458.5(FLNC):c.8129G>A (p.Trp2710Ter)	FLNC	Pathogenic	criteria provided, multiple submitters, no conflicts
4728	NM_001368067.1(LDB3):c.494C>T (p.Ala165Val)	LDB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5836	NM_006790.3(MYOT):c.179C>G (p.Ser60Cys)	PKD2L2-DT	Pathogenic	criteria provided, multiple submitters, no conflicts
44265	NM_001927.4(DES):c.638C>T (p.Ala213Val)	DES	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
66413	NM_001927.4(DES):c.46C>T (p.Arg16Cys)	DES	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374046	NM_001005361.3(DNM2):c.949T>C (p.Phe317Leu)	DNM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2937798	NM_001458.5(FLNC):c.6500T>C (p.Met2167Thr)	FLNC-AS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
253222	NM_007078.3(LDB3):c.869C>T (p.Pro290Leu)	LDB3	Uncertain significance	criteria provided, single submitter
39466	NM_004281.3(BAG3):c.772C>T (p.Arg258Trp)	BAG3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
44269	NM_001927.4(DES):c.735+20C>T	DES	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 18 · 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
BAG3	Definitive	Unknown	myofibrillar myopathy	13
FLNC	Definitive	Autosomal dominant	myofibrillar myopathy 5	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLNC	Orphanet:171445	Muscle filaminopathy
FLNC	Orphanet:63273	FLNC-related handgrip and calf weakness-distal myopathy
FLNC	Orphanet:75249	Familial isolated restrictive cardiomyopathy
BAG3	Orphanet:154	Familial isolated dilated cardiomyopathy
BAG3	Orphanet:199340	BAG3-related myofibrillar myopathy
LDB3	Orphanet:154	Familial isolated dilated cardiomyopathy
LDB3	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LDB3	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LDB3	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LDB3	Orphanet:54260	Left ventricular noncompaction
LDB3	Orphanet:98912	Late-onset distal myopathy, Markesbery-Griggs type
DES	Orphanet:154	Familial isolated dilated cardiomyopathy
DES	Orphanet:85146	Neurogenic scapuloperoneal syndrome, Kaeser type
DES	Orphanet:98909	Desminopathy
DNM2	Orphanet:100044	Autosomal dominant intermediate Charcot-Marie-Tooth disease type B
DNM2	Orphanet:169189	Autosomal dominant centronuclear myopathy
DNM2	Orphanet:228179	Autosomal dominant Charcot-Marie-Tooth disease type 2M
DNM2	Orphanet:363409	Fetal akinesia-cerebral and retinal hemorrhage syndrome

Cohort genes → proteins

7 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLNC	HGNC:3756	ENSG00000128591	Q14315	Filamin-C	gencc,clinvar
BAG3	HGNC:939	ENSG00000151929	O95817	BAG family molecular chaperone regulator 3	gencc,clinvar
LDB3	HGNC:15710	ENSG00000122367	O75112	LIM domain-binding protein 3	clinvar
DES	HGNC:2770	ENSG00000175084	P17661	Desmin	clinvar
DNM2	HGNC:2974	ENSG00000079805	P50570	Dynamin-2	clinvar
FLNC-AS1	HGNC:53474	ENSG00000242902		FLNC antisense RNA 1	clinvar
PKD2L2-DT	HGNC:55557	ENSG00000250159		PKD2L2 divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLNC	Filamin-C	Muscle-specific filamin, which plays a central role in sarcomere assembly and organization.
BAG3	BAG family molecular chaperone regulator 3	Co-chaperone and adapter protein that connects different classes of molecular chaperones including heat shock proteins 70 (HSP70s), e.g.
LDB3	LIM domain-binding protein 3	May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton.
DES	Desmin	Muscle-specific type III intermediate filament essential for proper muscular structure and function.
DNM2	Dynamin-2	Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission at plasma membrane during endocytosis and filament remodeling at many actin structures during organization of the actin cytoskeleton.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 3 · Druggable fraction: 0.14

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
Scaffold/PPI	2	4.9×	0.231
Antibody/Immunoglobulin	1	4.2×	0.433
Transcription factor	1	1.2×	0.793
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLNC	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
BAG3	Scaffold/PPI	no		WW_dom, BAG_domain, WW_dom_sf
LDB3	Transcription factor	no		PDZ, Znf_LIM, Zasp-like_motif
DES	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
DNM2	Scaffold/PPI	no	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, PH_domain
FLNC-AS1	Other/Unknown	no
PKD2L2-DT	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 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
hindlimb stylopod muscle	4
gastrocnemius	3
apex of heart	3
tibialis anterior	1
body of tongue	1
skeletal muscle tissue of rectus abdominis	1
skeletal muscle tissue of biceps brachii	1
saphenous vein	1
granulocyte	1
metanephros cortex	1
mucosa of transverse colon	1
muscle of leg	1
male germ line stem cell (sensu Vertebrata) in testis	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLNC	255	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, tibialis anterior
BAG3	286	ubiquitous	marker	gastrocnemius, skeletal muscle tissue of rectus abdominis, body of tongue
LDB3	247	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, apex of heart
DES	280	broad	marker	apex of heart, saphenous vein, gastrocnemius
DNM2	234	ubiquitous	marker	metanephros cortex, granulocyte, mucosa of transverse colon
FLNC-AS1	114		yes	hindlimb stylopod muscle, apex of heart, muscle of leg
PKD2L2-DT	135		yes	skeletal muscle tissue, hindlimb stylopod muscle, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BAG3	4,957
DNM2	4,715
FLNC	3,174
DES	2,486
LDB3	1,275
FLNC-AS1	0
PKD2L2-DT	0

Intra-cohort edges

A	B	Sources
BAG3	DNM2	intact
BAG3	FLNC	string_interaction
BAG3	LDB3	string_interaction
FLNC	LDB3	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNC	Q14315	14
LDB3	O75112	2
DNM2	P50570	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DES	P17661	77.73
BAG3	O95817	57.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
NOSTRIN mediated eNOS trafficking	1	571.0×	0.021	DNM2
Formation of annular gap junctions	1	259.6×	0.021	DNM2
Gap junction degradation	1	237.9×	0.021	DNM2
Retrograde neurotrophin signalling	1	203.9×	0.021	DNM2
Cell-extracellular matrix interactions	1	167.9×	0.021	FLNC
Cellular response to heat stress	1	98.5×	0.028	BAG3
Lysosome Vesicle Biogenesis	1	81.6×	0.028	DNM2
Striated Muscle Contraction	1	77.2×	0.028	DES
NGF-stimulated transcription	1	71.4×	0.028	DNM2
Recycling pathway of L1	1	56.0×	0.030	DNM2
Golgi Associated Vesicle Biogenesis	1	50.1×	0.030	DNM2
Degradation of CDH1	1	49.2×	0.030	DNM2
Regulation of HSF1-mediated heat shock response	1	34.8×	0.039	BAG3
Toll Like Receptor 4 (TLR4) Cascade	1	32.8×	0.039	DNM2
MHC class II antigen presentation	1	22.3×	0.052	DNM2
Clathrin-mediated endocytosis	1	21.3×	0.052	DNM2
Cellular responses to stress	1	9.2×	0.110	BAG3
Cellular responses to stimuli	1	7.9×	0.121	BAG3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sarcomere organization	2	153.2×	0.004	FLNC, LDB3
striated muscle cell apoptotic process	1	3370.4×	0.006	BAG3
vesicle scission	1	1685.2×	0.006	DNM2
negative regulation of membrane tubulation	1	1685.2×	0.006	DNM2
negative regulation of striated muscle cell apoptotic process	1	1123.5×	0.006	BAG3
actin filament bundle organization	1	1123.5×	0.006	DNM2
membrane tubulation	1	1123.5×	0.006	DNM2
protein transport along microtubule	1	1123.5×	0.006	BAG3
synaptic vesicle budding from presynaptic endocytic zone membrane	1	674.1×	0.008	DNM2
chaperone-mediated autophagy	1	561.7×	0.008	BAG3
aggresome assembly	1	561.7×	0.008	BAG3
obsolete negative regulation of protein targeting to mitochondrion	1	561.7×	0.008	BAG3
positive regulation of aggrephagy	1	561.7×	0.008	BAG3
skeletal muscle organ development	1	421.3×	0.009	DES
transferrin transport	1	306.4×	0.012	DNM2
muscle structure development	1	280.9×	0.012	LDB3
regulation of axon extension	1	259.3×	0.012	DNM2
post-Golgi vesicle-mediated transport	1	210.7×	0.013	DNM2
nuclear envelope organization	1	198.3×	0.013	DES
cellular response to unfolded protein	1	198.3×	0.013	BAG3
protein polymerization	1	198.3×	0.013	DNM2
synaptic vesicle transport	1	168.5×	0.015	DNM2
positive regulation of protein export from nucleus	1	160.5×	0.015	BAG3
stress fiber assembly	1	153.2×	0.015	DNM2
muscle cell cellular homeostasis	1	129.6×	0.017	BAG3
antigen processing and presentation of exogenous peptide antigen via MHC class II	1	108.7×	0.019	DNM2
spinal cord development	1	102.1×	0.019	BAG3
membrane organization	1	102.1×	0.019	DNM2
regulation of heart contraction	1	99.1×	0.019	DES
extrinsic apoptotic signaling pathway in absence of ligand	1	93.6×	0.020	BAG3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 7 evidence-associated genes (29%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLNC	0	0
BAG3	0	0
LDB3	0	0
DES	0	0
DNM2	0	0
FLNC-AS1	0	0
PKD2L2-DT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DNM2	15	Binding:15
BAG3	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNM2	3.6.5.5	dynamin GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	0
E	Difficult family or no structure, no drug	6	BAG3, LDB3, DES, DNM2, FLNC-AS1, PKD2L2-DT

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)
FLNC	0	—
BAG3	8	—
LDB3	0	—
DES	0	—
DNM2	15	—
FLNC-AS1	0	—
PKD2L2-DT	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
NCT07502989	Not specified	RECRUITING	Muscle Health Measurements Using Electrical Impedance Myography