MYOT

Summary

MYOT (myotilin, HGNC:12399) is a protein-coding gene on chromosome 5q31.2, encoding Myotilin (Q9UBF9). Component of a complex of multiple actin cross-linking proteins.

This gene encodes a cystoskeletal protein which plays a significant role in the stability of thin filaments during muscle contraction. This protein binds F-actin, crosslinks actin filaments, and prevents latrunculin A-induced filament disassembly. Mutations in this gene have been associated with limb-girdle muscular dystrophy and myofibrillar myopathies. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.

Source: NCBI Gene 9499 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myofibrillar myopathy 3 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 319 total — 4 likely-pathogenic
• Phenotypes (HPO): 49
• MANE Select transcript: NM_006790

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12399
Approved symbol	MYOT
Name	myotilin
Location	5q31.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000120729
Ensembl biotype	protein_coding
OMIM	604103
Entrez	9499

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000239926, ENST00000421631, ENST00000503748, ENST00000508938, ENST00000509812, ENST00000511254, ENST00000511625, ENST00000515645, ENST00000968642, ENST00000968643, ENST00000968644

RefSeq mRNA: 3 — MANE Select: NM_006790 NM_001135940, NM_001300911, NM_006790

CCDS: CCDS4194, CCDS47268, CCDS75309

Canonical transcript exons

ENST00000239926 — 10 exons

Exon	Start	End
ENSE00000453168	137886048	137886213
ENSE00000764008	137886864	137886997
ENSE00001196180	137870441	137871007
ENSE00001846550	137887213	137887851
ENSE00002085404	137867860	137867953
ENSE00003473626	137880816	137880865
ENSE00003484439	137883384	137883591
ENSE00003501635	137881973	137882105
ENSE00003545480	137877520	137877621
ENSE00003546105	137875829	137876003

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 99.70.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 7.8999 / max 2848.6891, expressed in 168 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58730	3.5240	61
58729	3.1958	80
58740	0.4723	132
58738	0.1518	25
58739	0.1090	21
58736	0.0831	17
58731	0.0683	13
58734	0.0682	17
58732	0.0536	13
58737	0.0518	19

Top tissues by expression

258 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	99.70	gold quality
gastrocnemius	UBERON:0001388	99.10	gold quality
muscle of leg	UBERON:0001383	98.82	gold quality
muscle organ	UBERON:0001630	98.16	gold quality
skeletal muscle organ	UBERON:0014892	98.16	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.81	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.52	gold quality
skeletal muscle tissue	UBERON:0001134	96.37	gold quality
biceps brachii	UBERON:0001507	96.36	gold quality
vastus lateralis	UBERON:0001379	96.01	gold quality
quadriceps femoris	UBERON:0001377	94.69	gold quality
body of tongue	UBERON:0011876	94.09	gold quality
buccal mucosa cell	CL:0002336	93.20	gold quality
calcaneal tendon	UBERON:0003701	91.03	gold quality
deltoid	UBERON:0001476	89.91	gold quality
muscle tissue	UBERON:0002385	89.79	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.54	gold quality
right atrium auricular region	UBERON:0006631	85.28	gold quality
tibialis anterior	UBERON:0001385	85.05	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.50	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.45	gold quality
lower esophagus	UBERON:0013473	84.41	gold quality
tibial nerve	UBERON:0001323	83.59	gold quality
heart left ventricle	UBERON:0002084	83.33	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	83.16	gold quality
cardiac atrium	UBERON:0002081	83.04	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.82	gold quality
cardiac ventricle	UBERON:0002082	81.90	gold quality
tongue	UBERON:0001723	81.55	gold quality
tendon	UBERON:0000043	80.70	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	33.94
E-MTAB-8410	yes	24.75
E-GEOD-135922	yes	22.40
E-CURD-46	yes	12.44
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

31 targeting MYOT, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-6797-3P	99.17	66.94	668
HSA-MIR-155-3P	99.03	67.99	924
HSA-MIR-6076	98.61	65.69	637
HSA-MIR-1246	98.54	66.21	959
HSA-MIR-649	97.96	67.21	704
HSA-MIR-376C-3P	97.63	68.88	1263
HSA-MIR-5194	96.77	63.91	1021
HSA-MIR-4703-3P	96.68	68.61	545
HSA-MIR-576-3P	96.14	65.63	773

Literature-anchored findings (GeneRIF, showing 22)

• A second known pedigree with LGMD1A: this finding constitutes a gold standard of proof that mutations in the myotilin gene cause Limb-Girdle Muscular Dystrophy 1A (PMID:12428213)
• Myotilin a thin filament-associated Z-disc protein.It binds to alpha-actinin and filamin c and is mutated in limb girdle muscular dystrophy 1A (LGMD1A).myotilin binds F-actin and prevents filament disassembly induced by Latrunculin A (PMID:12499399)
• Mutations in myotilin cause MFM; exon 2 of MYOT is a hotspot for mutations; peripheral neuropathy, cardiomyopathy, and distal weakness greater than proximal weakness are part of the spectrum of myotilinopathy; not all cases have a limb-girdle phenotype (PMID:15111675)
• Our findings provide evidence for a novel connection between the Z-disc protein myotilin and the sarcolemma via filamins and beta1 integrins. (PMID:16076904)
• The function of the myotilin protein is studied with regards its actin-organizing properties. (PMID:16122733)
• A novel mutation in the myotilin gene results in the clinical and pathologic phenotype termed “spheroid body myopathy.” Mutations in this gene also cause limb-girdle muscular dystrophy 1A and are associated with myofibrillar myopathy. (PMID:16380616)
• Mutations within the MYOT gene are not a cause for Vocal Cord and Pharyngeal Weakness with Distal Myopathy (VCPDM). (PMID:16674563)
• multigenerational French family in which gene sequencing identified a S60F myotilin mutation in all patients with full penetrance despite very late onset (PMID:16793270)
• Myotilin mutations promote aggregate-dependent contractile dysfunction similar to Limb-girdle Muscular Dystrophy type 1A and Myofibrillar Myopathy. (PMID:16801328)
• Myotilin S55F mutations may cause a clinically distinct autosomal-dominant late-onset and lower-limb distal myopathic syndrome. MRI helps to depict the topography of fatty muscle atrophy and to detect gene mutation carriers. (PMID:17698502)
• new autosomal dominant kindred with generalized symmetrical increase in muscle bulk (PMID:19027924)
• This is the first report of a binding motif common to both the myotilin and the FATZ (calsarcin/myozenin) families that is specific for interactions with Enigma family members. (PMID:19047374)
• Data show that in myofibrillar myopathies myotilin exhibites significant alterations in their localization. (PMID:19151983)
• study presents high-resolution structure of the first Ig-domain of myotilin determined with solution state NMR spectroscopy; structure of MyoIg1 exhibits I-type Ig-fold (PMID:19418025)
• identified a novel MYOT mutation in Exon 9 encoding the second immunoglobulin-like domain in 1 patient with clinically typical limb girdle muscular dystrophy (PMID:19458539)
• Analysis of myotilin turnover provides mechanistic insight into the role of myotilinopathy-causing mutations (PMID:21361873)
• Describe the first homozygous mutation in the myotilin gene leading to a novel, autosomal recessive subtype of myofibrillar myopathy (MFM). (PMID:24928145)
• A French family affected with a late onset proximal and distal muscle weakness and myofibrillar myopathy on muscle pathology, in which the siblings known to be clinically affected were homozygous for the c.179C>T (p.Ser60Phe) myotilin gene mutation is reported. (PMID:27854214)
• sequence conservation analysis of myotilin shed light on the molecular basis of myotilinopathies and revealed several motifs in Ig domains found also in I-band proteins. (PMID:28638118)
• Silencing MYOT Expression May Inhibit Autophagy in Human Skeletal Muscle Cells. (PMID:36776921)
• Human Mutated MYOT and CRYAB Genes Cause a Myopathic Phenotype in Zebrafish. (PMID:37511242)
• A novel in-frame deletion in MYOT causes an early adult onset distal myopathy. (PMID:37553249)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	myot	ENSDARG00000076312
mus_musculus	Myot	ENSMUSG00000024471
rattus_norvegicus	Myot	ENSRNOG00000047186
drosophila_melanogaster	bt	FBGN0005666
caenorhabditis_elegans		WBGENE00001000
caenorhabditis_elegans		WBGENE00006759

Paralogs (9): SPEG (ENSG00000072195), PALLD (ENSG00000129116), ALPK3 (ENSG00000136383), MYPN (ENSG00000138347), HMCN1 (ENSG00000143341), OBSCN (ENSG00000154358), IGFN1 (ENSG00000163395), CCDC141 (ENSG00000163492), SPEGNB (ENSG00000286095)

Protein

Protein identifiers

Myotilin — Q9UBF9 (reviewed: Q9UBF9)

Alternative names: 57 kDa cytoskeletal protein, Myofibrillar titin-like Ig domains protein, Titin immunoglobulin domain protein

All UniProt accessions (3): A0A0C4DFM5, B4DT68, Q9UBF9

UniProt curated annotations — full annotation on UniProt →

Function. Component of a complex of multiple actin cross-linking proteins. Involved in the control of myofibril assembly and stability at the Z lines in muscle cells.

Subunit / interactions. Homodimer. Interacts with ACTA1, ACTN1, FLNA, FLNB, FLNC and MYOZ2. Interacts with the C-terminal region of MYOZ1.

Subcellular location. Cell membrane. Sarcolemma. Cytoplasm. Cytoskeleton. Myofibril. Sarcomere. Z line.

Tissue specificity. Expressed in skeletal muscle (at protein level). Expressed in skeletal muscle, heart, bone marrow and thyroid gland.

Disease relevance. Myopathy, myofibrillar, 3 (MFM3) [MIM:609200] A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM3 is characterized by progressive skeletal muscle weakness greater distally than proximally, tight heel cords, hyporeflexia, cardiomyopathy and peripheral neuropathy in some patients. Affected muscle exhibits disorganization and streaming of the Z-line, presence of large hyaline structures, excessive accumulation of myotilin and other ectopically expressed proteins and prominent congophilic deposits. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the myotilin/palladin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBF9-1	1	yes
Q9UBF9-2	2

RefSeq proteins (3): NP_001129412, NP_001287840, NP_006781* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF07679

UniProt features (46 total): strand 19, sequence variant 9, region of interest 6, compositionally biased region 4, domain 2, helix 2, chain 1, modified residue 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2KDG	SOLUTION NMR
2KKQ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBF9-F1	65.17	0.35

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 20

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 204 (showing top): GCANCTGNY_MYOD_Q6, GOBP_NEUROGENESIS, CAGCTG_AP4_Q5, GOBP_CELL_CELL_ADHESION, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_MUSCLE_CONTRACTION, BLALOCK_ALZHEIMERS_DISEASE_UP, TGACATY_UNKNOWN, GATA1_04, LYF1_01, SABATES_COLORECTAL_ADENOMA_DN, GOMF_ACTIN_BINDING, GOBP_MUSCLE_SYSTEM_PROCESS, GOCC_NEURON_PROJECTION

GO Biological Process (4): muscle contraction (GO:0006936), homophilic cell-cell adhesion (GO:0007156), synapse organization (GO:0050808), axon guidance (GO:0007411)

GO Molecular Function (5): actin binding (GO:0003779), axon guidance receptor activity (GO:0008046), structural constituent of muscle (GO:0008307), alpha-actinin binding (GO:0051393), protein binding (GO:0005515)

GO Cellular Component (9): plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), Z disc (GO:0030018), axon (GO:0030424), sarcolemma (GO:0042383), neuronal cell body (GO:0043025), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
muscle system process	1
cell-cell adhesion	1
cell junction organization	1
axonogenesis	1
neuron projection guidance	1
cytoskeletal protein binding	1
transmembrane signaling receptor activity	1
axon guidance	1
structural molecule activity	1
actinin binding	1
binding	1
membrane	1
cell periphery	1
cytoskeleton	1
I band	1
neuron projection	1
plasma membrane	1
somatodendritic compartment	1
cell body	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1290 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MYOT	FLNC	Q14315	998
MYOT	MYOZ1	Q9NP98	978
MYOT	LDB3	O75112	946
MYOT	ACTN2	P35609	910
MYOT	BAG3	O95817	894
MYOT	MYOZ2	Q9NPC6	877
MYOT	TCAP	O15273	861
MYOT	CRYAB	P02511	851
MYOT	DMD	P11532	826
MYOT	ACTN3	Q08043	817
MYOT	ACTA1	P02568	791
MYOT	SELENON	Q9NZV5	788
MYOT	NEB	P20929	752
MYOT	PLEC	Q15149	751
MYOT	ACTN1	P12814	716

IntAct

144 interactions, top by confidence:

A	B	Type	Score
MYOT	FLNC	psi-mi:“MI:0915”(physical association)	0.580
FLNC	MYOT	psi-mi:“MI:0915”(physical association)	0.580
MYOT	NME7	psi-mi:“MI:0915”(physical association)	0.560
NME7	MYOT	psi-mi:“MI:0915”(physical association)	0.560
MYOT	ACTN2	psi-mi:“MI:0915”(physical association)	0.560
ACTN3	MYOT	psi-mi:“MI:0915”(physical association)	0.560
PFDN5	MYOT	psi-mi:“MI:0915”(physical association)	0.560
MYOT	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	PDLIM1	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	GRIP2	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (23): MYOT (Two-hybrid), MYOT (Two-hybrid), NME7 (Two-hybrid), MYOT (Synthetic Growth Defect), MYOT (Reconstituted Complex), MYOT (Two-hybrid), MYOT (Two-hybrid), ACTN2 (Two-hybrid), ACTN1 (Two-hybrid), MYOT (Affinity Capture-MS), PFDN5 (Two-hybrid), ACTN3 (Two-hybrid), MYOT (Two-hybrid), MYOT (Two-hybrid), MYOT (Affinity Capture-Western)

ESM2 similar proteins: A2ASS6, A8DYP0, E9QMW4, G4SLH0, J7M799, M9MRD1, O15061, O43491, O55103, O70318, O75952, O77788, P07197, P08553, P08855, P11799, P12839, P16053, P27321, P51125, P54938, P57786, P82179, P83741, Q06637, Q13061, Q23551, Q28820, Q4R3X7, Q63425, Q66H38, Q696W0, Q6TS35, Q70IV5, Q7Z589, Q7ZUV7, Q86TC9, Q8BMB0, Q8TC56, Q8WZ42

Diamond homologs: A0A5K1K8H0, A4IFM7, A7SNN5, A8C984, A8WRV1, A8XQD5, D3ZHP7, E9PT87, F1M0Z1, O01761, O02827, O14936, O15865, O43293, O44997, O45818, O54784, O55005, O65554, O70150, O70589, O75962, O88764, O94768, O94806, P00518, P05986, P07313, P0C5E3, P11275, P11798, P20689, P25323, P29294, P34099, P53355, P70193, Q0KHT7, Q0KL02, Q12263

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	6	58.1×	4e-08
Unblocking of NMDA receptors, glutamate binding and activation	6	55.3×	4e-08
Negative regulation of NMDA receptor-mediated neuronal transmission	6	55.3×	4e-08
Long-term potentiation	6	48.4×	8e-08
Assembly and cell surface presentation of NMDA receptors	9	38.7×	3e-10
Neurexins and neuroligins	8	26.7×	4e-08
RAF/MAP kinase cascade	6	6.2×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
receptor clustering	8	60.2×	3e-10
establishment or maintenance of epithelial cell apical/basal polarity	8	56.0×	3e-10
protein localization to synapse	5	46.1×	5e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	6	35.8×	2e-06
cell-cell adhesion	10	12.2×	1e-06
protein-containing complex assembly	8	11.0×	4e-05
actin cytoskeleton organization	8	7.6×	4e-04
chemical synaptic transmission	7	6.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

319 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	4
Uncertain significance	178
Likely benign	76
Benign	22

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
3065290	NM_006790.3(MYOT):c.634C>T (p.Gln212Ter)	Likely pathogenic
3390979	NM_006790.3(MYOT):c.145_149del (p.Glu49fs)	Likely pathogenic
4277727	NM_006790.3(MYOT):c.531+1G>A	Likely pathogenic
4687901	NM_006790.3(MYOT):c.1111C>T (p.Gln371Ter)	Likely pathogenic

SpliceAI

1099 predictions. Top by Δscore:

Variant	Effect	Δscore
5:137867952:GG:G	donor_gain	1.0000
5:137867953:GG:G	donor_gain	1.0000
5:137875957:A:T	donor_gain	1.0000
5:137875977:G:GT	donor_gain	1.0000
5:137875996:G:GT	donor_gain	1.0000
5:137875997:A:T	donor_gain	1.0000
5:137876004:G:GG	donor_gain	1.0000
5:137877507:A:AG	acceptor_gain	1.0000
5:137877508:A:G	acceptor_gain	1.0000
5:137877516:A:AG	acceptor_gain	1.0000
5:137877516:AAAGC:A	acceptor_gain	1.0000
5:137877517:A:G	acceptor_gain	1.0000
5:137877519:GC:G	acceptor_gain	1.0000
5:137880807:A:AG	acceptor_gain	1.0000
5:137880813:A:AG	acceptor_gain	1.0000
5:137880814:A:G	acceptor_gain	1.0000
5:137882277:C:G	donor_gain	1.0000
5:137883379:TCTA:T	acceptor_loss	1.0000
5:137883381:TAGGT:T	acceptor_loss	1.0000
5:137883383:G:A	acceptor_loss	1.0000
5:137883383:GGT:G	acceptor_gain	1.0000
5:137883383:GGTGA:G	acceptor_gain	1.0000
5:137886863:GCTT:G	acceptor_gain	1.0000
5:137887212:GCAC:G	acceptor_gain	1.0000
5:137867951:CGGGT:C	donor_loss	0.9900
5:137867952:GGGTA:G	donor_loss	0.9900
5:137867953:GGTAA:G	donor_loss	0.9900
5:137867954:GTAAG:G	donor_loss	0.9900
5:137867955:T:A	donor_loss	0.9900
5:137870511:G:GT	donor_gain	0.9900

AlphaMissense

3255 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:137883414:T:A	W283R	1.000
5:137883414:T:C	W283R	1.000
5:137883548:T:A	N327K	1.000
5:137883548:T:G	N327K	1.000
5:137886167:T:A	W382R	1.000
5:137886167:T:C	W382R	1.000
5:137886934:T:G	Y421D	1.000
5:137882038:C:A	P250Q	0.999
5:137882044:T:C	F252S	0.999
5:137883391:G:A	G275E	0.999
5:137883415:G:C	W283S	0.999
5:137883486:T:C	S307P	0.999
5:137883490:T:C	L308P	0.999
5:137883528:T:G	Y321D	0.999
5:137883534:T:C	C323R	0.999
5:137883536:T:G	C323W	0.999
5:137883540:G:C	A325P	0.999
5:137883541:C:A	A325D	0.999
5:137883561:G:C	A332P	0.999
5:137886075:T:C	F351S	0.999
5:137886126:T:C	L368P	0.999
5:137886131:T:C	C370R	0.999
5:137886168:G:C	W382S	0.999
5:137886169:G:C	W382C	0.999
5:137886169:G:T	W382C	0.999
5:137886935:A:C	Y421S	0.999
5:137886943:T:C	S424P	0.999
5:137886954:T:A	N427K	0.999
5:137886954:T:G	N427K	0.999
5:137886986:T:C	L438S	0.999

dbSNP variants (sampled 300 via entrez): RS1000182750 (5:137879574 G>C,T), RS1000581526 (5:137885836 C>G,T), RS1000618188 (5:137879235 C>A,T), RS1000890279 (5:137879023 C>T), RS1000919643 (5:137877744 C>CAT), RS1001034154 (5:137885448 C>A), RS1001063709 (5:137885228 G>A), RS1001318394 (5:137871278 G>GA), RS1001489004 (5:137886577 C>T), RS1001511934 (5:137886241 T>C), RS1001530536 (5:137870049 G>C,T), RS1001559945 (5:137870586 C>T), RS1001706381 (5:137885381 A>C,G), RS1001780124 (5:137885742 A>G), RS1001848764 (5:137884715 TA>T,TAA)

Disease associations

OMIM: gene MIM:604103 | disease phenotypes: MIM:159000, MIM:182920, MIM:609200

GenCC curated gene-disease

Disease	Classification	Inheritance
myofibrillar myopathy 3	Strong	Autosomal dominant
spheroid body myopathy	Supportive	Autosomal dominant

Mondo (3): myofibrillar myopathy 3 (MONDO:0012215), heart failure (MONDO:0005252), (MONDO:0008448)

Orphanet (3): Autosomal dominant limb-girdle muscular dystrophy type 1A (Orphanet:266), Spheroid body myopathy (Orphanet:268129), Distal myotilinopathy (Orphanet:98911)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000297	Facial hypotonia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001271	Polyneuropathy
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001611	Hypernasal speech
HP:0001638	Cardiomyopathy
HP:0001771	Achilles tendon contracture
HP:0002015	Dysphagia
HP:0002093	Respiratory insufficiency
HP:0002460	Distal muscle weakness
HP:0002540	Inability to walk
HP:0002600	Hyporeflexia of lower limbs
HP:0002792	Reduced vital capacity
HP:0002795	Abnormal respiratory system physiology
HP:0002828	Multiple joint contractures
HP:0002878	Respiratory failure
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003326	Myalgia
HP:0003458	EMG: myopathic abnormalities
HP:0003547	Shoulder girdle muscle weakness
HP:0003551	Difficulty climbing stairs
HP:0003552	Muscle stiffness
HP:0003555	Muscle fiber splitting
HP:0003557	Increased variability in muscle fiber diameter
HP:0003581	Adult onset
HP:0003677	Slowly progressive
HP:0003687	Centrally nucleated skeletal muscle fibers

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001969_32	Heart rate	3.000000e-07
GCST005356_12	Severe malaria	6.000000e-07
GCST005357_8	Severe malaria (adjusted for sickle cell variant rs334)	2.000000e-06
GCST006414_139	Atrial fibrillation	1.000000e-35

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006333	Heart Failure	C14.280.434
C535906	Muscular dystrophy, limb-girdle, type 1A (supp.)
C563775	Myotilinopathy (supp.)
C000598645	Spheroid body myopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	2
Doxorubicin	decreases expression, increases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	increases expression, affects cotreatment	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
CGP 52608	increases reaction, affects binding	1
torcetrapib	increases expression	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	increases expression	1
Chenodeoxycholic Acid	affects cotreatment, increases expression	1
Deoxycholic Acid	affects cotreatment, increases expression	1
Estradiol	affects binding, increases expression	1
Etoposide	increases expression	1
Glycochenodeoxycholic Acid	increases expression, affects cotreatment	1
Glycocholic Acid	increases expression, affects cotreatment	1
Glycodeoxycholic Acid	affects cotreatment, increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Nickel	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00083772	PHASE4	TERMINATED	Use of Nesiritide in the Management of Acute Diastolic Heart Failure
NCT00146848	PHASE4	COMPLETED	PEGASUS CRT Study: Atrial Support Study in Cardiac Resynchronization Therapy
NCT00154115	PHASE4	COMPLETED	Levosimendan in High Risk Heart Valve Surgery
NCT00170313	PHASE4	TERMINATED	CORE: Study to Evaluate the Conducted AF-Response-Algorithm in Patients Suffering From Heart Failure and Atrial Fibrillation
NCT00180596	PHASE4	COMPLETED	PACMAN - PAcing for CardioMyopathies, a EuropeAN Study
NCT00187200	PHASE4	COMPLETED	Response of Cardiac Resynchronization Therapy Optimization With Ventricle to Ventricle Timing in Heart Failure Patients
NCT00206232	PHASE4	COMPLETED	Novel Treatment for Diastolic Heart Failure in Women
NCT00206856	PHASE4	TERMINATED	Rapid Assessment of Bedside BNP In Treatment of Heart Failure (RABBIT)
NCT00219388	PHASE4	COMPLETED	Efficacy and Safety of Treatment With Simdax® Versus Dobutrex® in Decompensated Heart Failure Patients.
NCT00288587	PHASE4	COMPLETED	Extracorporeal Ultrafiltration (UF) vs. Usual and Customary Care for Patients With Severe Heart Failure (HF)
NCT00305526	PHASE4	TERMINATED	REBEAT Resynchronisation and Beta-Blocker European Trial
NCT00324766	PHASE4	COMPLETED	Levosimendan in Acute Heart Failure Following Acute Myocardial Infarction.
NCT00347087	PHASE4	COMPLETED	Effect of Irbesartan on Insulin Sensitivity in Chronic Heart Failure
NCT00371085	PHASE4	COMPLETED	Congestive Heart Failure Outreach Program
NCT00384566	PHASE4	WITHDRAWN	A Comparison of the Effect of Carvedilol and Metoprolol on Airways Tone in Patients With Heart Failure
NCT00391846	PHASE4	COMPLETED	Evaluation of Heart Failure Treatment Guided by N-terminal Pro B-type Natriuretic Peptide (NTproBNP) vs Clinical Symptoms and Signs Alone
NCT00400582	PHASE4	COMPLETED	A Pharmacogenomic Study of Candesartan in Heart Failure
NCT00402376	PHASE4	TERMINATED	Evaluation of Myocardial Improvement in Patients Supported by Ventricular Assist Device Under Optimal Pharmacological Therapy
NCT00418119	PHASE4	UNKNOWN	Erythropoietin Treatment in Patients With Systolic Left Ventricular Dysfunction, Mild Anemia and Normal Renal Function
NCT00422318	PHASE4	COMPLETED	Treatment of Hyperuricemia in Patients With Heart Failure
NCT00477789	PHASE4	COMPLETED	Effects of Allopurinol on Diastolic Function in Chronic Heart Failure Patients
NCT00480077	PHASE4	TERMINATED	Diagnostic Outcome Trial in Heart Failure (DOT-HF Trial)
NCT00489177	PHASE4	COMPLETED	Optimal Programming to Improve Mechanical Indices, Symptoms and Exercise in Cardiac Resynchronization Therapy.
NCT00491907	PHASE4	TERMINATED	Effect of Folic Acid on Endothelial and Baroreceptor Function in Patients With Heart Failure
NCT00497900	PHASE4	COMPLETED	The Effect of Calcium and Vitamin D in Patients With Heart Failure
NCT00498472	PHASE4	COMPLETED	NT-proBNP in the Optimization of Treatment After Recent Acute Heart Failure Trial
NCT00512759	PHASE4	COMPLETED	Goal-directed Afterload Reduction in Acute Congestive Cardiac Decompensation Study
NCT00517426	PHASE4	COMPLETED	Effects of Acetazolamide and CO2 Inhalation on Exercise-induced Periodic Breathing in Heart Failure
NCT00517725	PHASE4	COMPLETED	Nebivolol Versus Bisoprolol Versus Carvedilol in Heart Failure
NCT00527059	PHASE4	UNKNOWN	Renal Effects of Levosimendan in Patients Admitted With Acute Decompensated Heart Failure
NCT00551499	PHASE4	COMPLETED	Cardiac Resynchronisation Therapy in Combination With Overdrive Pacing in the Treatment of Central Sleep Apnea in CHF
NCT00552851	PHASE4	UNKNOWN	Changes of Left Ventricular Mass and Cardiac Function in Patients With Active Acromegaly During Treatment With the Growth Hormone Receptor Antagonist Pegvisomant
NCT00574119	PHASE4	COMPLETED	Effect of Aldosterone on Energy Starvation in Heart Failure
NCT00613964	PHASE4	TERMINATED	The Effects of Carperitide on Short and Long-term Prognosis in Patients With Both Cardiac and Renal Failure
NCT00643188	PHASE4	COMPLETED	Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF
NCT00652652	PHASE4	COMPLETED	Evaluation of Combined Action Between Natrecor and Furosemide on Kidney and Neurohormone Responses in Chronic Heart Failure: A Phase-IV study704.351 / DSS
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00663377	PHASE4	COMPLETED	Effects of Losartan on Insulin Resistance in Patients With Heart Failure
NCT00664339	PHASE4	COMPLETED	Flu Vaccination in Congestive Heart Failure
NCT00668408	PHASE4	UNKNOWN	LTOT in COPD Patients With Moderate Chronic Hypoxemia and Chronic Heart Failure