Myofibrillar myopathy 6

Summary

Myofibrillar myopathy 6 (MONDO:0013061) is a disease caused by BAG3 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BAG3 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,167

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	myofibrillar myopathy 6
Mondo ID	MONDO:0013061
MeSH	C567843
OMIM	612954
Orphanet	199340
DOID	DOID:0080097
UMLS	C2751831
MedGen	414119
GARD	0017096
Is cancer (heuristic)	no

Also known as: BAG3 myofibrillar myopathy (disease) · MFM6 · myofibrillar myopathy (disease) caused by mutation in BAG3 · myofibrillar myopathy 6 · myofibrillar myopathy type 6 · myopathy, myofibrillar, 6 · myopathy, myofibrillar, type 6

Data availability: 1,167 ClinVar variants · 4 GenCC gene-disease records · 8 cell lines.

Disease family

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 › myofibrillar myopathy 6

Related subtypes (12): central core myopathy, myofibrillar myopathy 1, myofibrillar myopathy 3, myofibrillar myopathy 4, myofibrillar myopathy 5, 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

600 retrieved; paginated sample, class counts are floors:

328 uncertain significance, 164 likely benign, 48 conflicting classifications of pathogenicity, 38 pathogenic, 9 pathogenic/likely pathogenic, 7 benign/likely benign, 3 likely pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066195	NM_004281.4(BAG3):c.1348A>T (p.Lys450Ter)	BAG3	Pathogenic	criteria provided, single submitter
1069307	NM_004281.4(BAG3):c.811C>T (p.Gln271Ter)	BAG3	Pathogenic	criteria provided, multiple submitters, no conflicts
1070601	NM_004281.4(BAG3):c.824del (p.Ser275fs)	BAG3	Pathogenic	criteria provided, single submitter
1075312	NM_004281.4(BAG3):c.351_352insTGGATGCAGCGATTCCGAACTGAGGCGGCAGCAGCGGCTCCTCAGAGGTCCCAGTCACCTCTGCGGGGCATGCCAGAAACCACTCAGCCAGATAAACAGCGTGGACAGGTGGCAGCGGCGGCGGCAGCCCAGCCCCCAGCCT (p.Gly118fs)	BAG3	Pathogenic	criteria provided, single submitter
1075572	NM_004281.4(BAG3):c.530_531del (p.Ala176_Ser177insTer)	BAG3	Pathogenic	criteria provided, single submitter
1076610	NM_004281.4(BAG3):c.654del (p.Pro219fs)	BAG3	Pathogenic	criteria provided, single submitter
1076893	NC_000010.10:g.(?121411178)(121437012_?)del	BAG3	Pathogenic	criteria provided, single submitter
1323968	NM_004281.4(BAG3):c.1353C>A (p.Tyr451Ter)	BAG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324072	NM_004281.4(BAG3):c.457C>T (p.Gln153Ter)	BAG3	Pathogenic	criteria provided, single submitter
1324087	NM_004281.4(BAG3):c.331_332del (p.Phe111fs)	BAG3	Pathogenic	criteria provided, single submitter
1324094	NM_004281.4(BAG3):c.361C>T (p.Arg121Ter)	BAG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324125	NM_004281.4(BAG3):c.1057del (p.Gln353fs)	BAG3	Pathogenic	criteria provided, single submitter
1324260	NM_004281.4(BAG3):c.910C>T (p.Gln304Ter)	BAG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1362749	NM_004281.4(BAG3):c.598C>T (p.Gln200Ter)	BAG3	Pathogenic	criteria provided, single submitter
1396666	NM_004281.4(BAG3):c.165del (p.Ser56fs)	BAG3	Pathogenic	criteria provided, single submitter
1398633	NM_004281.4(BAG3):c.640C>T (p.Gln214Ter)	BAG3	Pathogenic	criteria provided, single submitter
1432977	NM_004281.4(BAG3):c.751C>T (p.Gln251Ter)	BAG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452208	NM_004281.4(BAG3):c.38_39dup (p.Ser14fs)	BAG3	Pathogenic	criteria provided, single submitter
1453625	NM_004281.4(BAG3):c.488del (p.Pro163fs)	BAG3	Pathogenic	criteria provided, single submitter
1455927	NC_000010.10:g.(?121411188)(121411387_?)del	BAG3	Pathogenic	criteria provided, single submitter
1456226	NM_004281.4(BAG3):c.1326dup (p.Glu443Ter)	BAG3	Pathogenic	criteria provided, single submitter
1456480	NM_004281.4(BAG3):c.766G>T (p.Glu256Ter)	BAG3	Pathogenic	criteria provided, single submitter
1457623	NC_000010.10:g.(?121435956)(121436794_?)del	BAG3	Pathogenic	criteria provided, single submitter
1494973	NM_004281.4(BAG3):c.1088_1708del (p.Glu363_Pro569del)	BAG3	Pathogenic	criteria provided, single submitter
156530	NM_004281.4(BAG3):c.626C>A (p.Pro209Gln)	BAG3	Pathogenic	criteria provided, single submitter
162769	NM_004281.4(BAG3):c.72del (p.Gly25fs)	BAG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675064	NM_004281.4(BAG3):c.612del (p.Tyr205fs)	BAG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1736414	NM_004281.4(BAG3):c.394C>T (p.Gln132Ter)	BAG3	Pathogenic	criteria provided, multiple submitters, no conflicts
1797440	NM_004281.4(BAG3):c.29_35del (p.Met10fs)	BAG3	Pathogenic	criteria provided, multiple submitters, no conflicts
179764	NM_004281.4(BAG3):c.1067del (p.Pro356fs)	BAG3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BAG3	Orphanet:154	Familial isolated dilated cardiomyopathy
BAG3	Orphanet:199340	BAG3-related myofibrillar myopathy
CD46	Orphanet:244242	HELLP syndrome
CD46	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BAG3	HGNC:939	ENSG00000151929	O95817	BAG family molecular chaperone regulator 3	gencc,clinvar
LPA	HGNC:6667	ENSG00000198670	P08519	Apolipoprotein(a)	clinvar
CD46	HGNC:6953	ENSG00000117335	P15529	Membrane cofactor protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
LPA	Apolipoprotein(a)	Apo(a) is the main constituent of lipoprotein(a) (Lp(a)).
CD46	Membrane cofactor protein	Acts as a cofactor for complement factor I, a serine protease which protects autologous cells against complement-mediated injury by cleaving C3b and C4b deposited on host tissue.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Complement	1	89.3×	0.033
Protease	1	12.2×	0.120
Scaffold/PPI	1	5.8×	0.164

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BAG3	Scaffold/PPI	no		WW_dom, BAG_domain, WW_dom_sf
LPA	Protease	yes		Kringle, Trypsin_dom, Peptidase_S1A
CD46	Complement	yes		Sushi_SCR_CCP_dom, CD46, Sushi/SCR/CCP_sf

Expression context

Cohort genes with no expression data: 0.

3 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
adrenal tissue	2
body of tongue	1
gastrocnemius	1
skeletal muscle tissue of rectus abdominis	1
liver	1
right lobe of liver	1
mucosa of paranasal sinus	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BAG3	286	ubiquitous	marker	gastrocnemius, skeletal muscle tissue of rectus abdominis, body of tongue
LPA	100	tissue_specific	marker	liver, right lobe of liver, adrenal tissue
CD46	295	ubiquitous	marker	palpebral conjunctiva, adrenal tissue, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BAG3	4,957
CD46	1,780
LPA	1,200

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LPA	P08519	16
CD46	P15529	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BAG3	O95817	57.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
LDL remodeling	1	634.4×	0.019	LPA
Complement cascade	1	211.5×	0.023	CD46
Plasma lipoprotein remodeling	1	158.6×	0.023	LPA
Cellular response to heat stress	1	131.3×	0.023	BAG3
Regulation of Complement cascade	1	77.7×	0.026	CD46
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.026	LPA
Regulation of HSF1-mediated heat shock response	1	46.4×	0.037	BAG3
Cellular responses to stress	1	12.3×	0.119	BAG3
Cellular responses to stimuli	1	10.5×	0.123	BAG3
Innate Immune System	1	8.5×	0.125	CD46
Transport of small molecules	1	8.4×	0.125	LPA
Immune System	1	4.3×	0.214	CD46

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
striated muscle cell apoptotic process	1	5617.3×	0.003	BAG3
obsolete sequestering of extracellular ligand from receptor	1	5617.3×	0.003	CD46
negative regulation of striated muscle cell apoptotic process	1	1872.4×	0.005	BAG3
protein transport along microtubule	1	1872.4×	0.005	BAG3
chaperone-mediated autophagy	1	936.2×	0.005	BAG3
aggresome assembly	1	936.2×	0.005	BAG3
obsolete negative regulation of protein targeting to mitochondrion	1	936.2×	0.005	BAG3
positive regulation of aggrephagy	1	936.2×	0.005	BAG3
negative regulation of complement activation, classical pathway	1	802.5×	0.005	CD46
positive regulation of transforming growth factor beta production	1	702.2×	0.006	CD46
positive regulation of memory T cell differentiation	1	624.1×	0.006	CD46
T cell mediated immunity	1	330.4×	0.009	CD46
cellular response to unfolded protein	1	330.4×	0.009	BAG3
positive regulation of regulatory T cell differentiation	1	312.1×	0.009	CD46
regulation of Notch signaling pathway	1	280.9×	0.009	CD46
positive regulation of protein export from nucleus	1	267.5×	0.009	BAG3
muscle cell cellular homeostasis	1	216.1×	0.011	BAG3
complement activation, classical pathway	1	181.2×	0.011	CD46
blood circulation	1	170.2×	0.011	LPA
spinal cord development	1	170.2×	0.011	BAG3
extrinsic apoptotic signaling pathway in absence of ligand	1	156.0×	0.012	BAG3
positive regulation of protein import into nucleus	1	140.4×	0.012	BAG3
extrinsic apoptotic signaling pathway via death domain receptors	1	133.8×	0.012	BAG3
positive regulation of interleukin-10 production	1	133.8×	0.012	CD46
cellular response to heat	1	114.6×	0.014	BAG3
lipid transport	1	87.8×	0.017	LPA
positive regulation of T cell proliferation	1	86.4×	0.017	CD46
autophagosome assembly	1	74.9×	0.019	BAG3
cellular response to mechanical stimulus	1	72.0×	0.019	BAG3
single fertilization	1	61.1×	0.021	CD46

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
BAG3	0	0
LPA	0	0
CD46	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
BAG3	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	LPA, CD46
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BAG3

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)
BAG3	8	—
LPA	0	—
CD46	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.