TCAP

Summary

TCAP (titin-cap, HGNC:11610) is a protein-coding gene on chromosome 17q12, encoding Telethonin (O15273). Muscle assembly regulating factor.

Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G.

Source: NCBI Gene 8557 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive limb-girdle muscular dystrophy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 386 total — 16 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 35
• MANE Select transcript: NM_003673

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11610
Approved symbol	TCAP
Name	titin-cap
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	T-cap, TELE, telethonin, CMD1N
Ensembl gene	ENSG00000173991
Ensembl biotype	protein_coding
OMIM	604488
Entrez	8557

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000309889, ENST00000578283

RefSeq mRNA: 1 — MANE Select: NM_003673 NM_003673

CCDS: CCDS11342

Canonical transcript exons

ENST00000309889 — 2 exons

Exon	Start	End
ENSE00000950649	39665716	39666554
ENSE00002719913	39665349	39665469

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 99.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 76.4888 / max 15172.6745, expressed in 143 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160594	76.3470	142
160595	0.0548	21
208169	0.0319	15
160593	0.0280	15
160592	0.0271	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.93	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.92	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.91	gold quality
right atrium auricular region	UBERON:0006631	99.88	gold quality
gastrocnemius	UBERON:0001388	99.84	gold quality
cardiac atrium	UBERON:0002081	99.84	gold quality
diaphragm	UBERON:0001103	99.80	gold quality
gluteal muscle	UBERON:0002000	99.75	gold quality
left ventricle myocardium	UBERON:0006566	99.72	gold quality
triceps brachii	UBERON:0001509	99.68	gold quality
heart left ventricle	UBERON:0002084	99.65	gold quality
cardiac ventricle	UBERON:0002082	99.63	gold quality
body of tongue	UBERON:0011876	99.63	gold quality
vastus lateralis	UBERON:0001379	99.57	gold quality
skeletal muscle tissue	UBERON:0001134	99.56	gold quality
quadriceps femoris	UBERON:0001377	99.55	gold quality
biceps brachii	UBERON:0001507	99.50	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.48	gold quality
tibialis anterior	UBERON:0001385	99.22	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.21	gold quality
myocardium	UBERON:0002349	99.05	gold quality
heart right ventricle	UBERON:0002080	98.93	gold quality
deltoid	UBERON:0001476	98.84	gold quality
vena cava	UBERON:0004087	98.73	gold quality
muscle organ	UBERON:0001630	98.31	gold quality
skeletal muscle organ	UBERON:0014892	98.31	gold quality
muscle of leg	UBERON:0001383	97.82	gold quality
muscle tissue	UBERON:0002385	97.10	gold quality
heart	UBERON:0000948	96.97	gold quality
tongue	UBERON:0001723	96.04	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	15241.20
E-ANND-3	yes	8.02

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYOD1, MYOG

miRNA regulators (miRDB)

11 targeting TCAP, 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-4283	100.00	66.42	2097
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656

Literature-anchored findings (GeneRIF, showing 23)

• review of telethonin and other new proteins of the Z-disc of skeletal muscle (PMID:11699871)
• telethonin protein levels seems to be at least in part regulated by neuronal activity and is thus linked to the dynamic control of myofibrillogenesis and muscle turnover in human skeletal muscle. (PMID:11763198)
• telethonin may play a role in linking titin filaments at the Z-disk periphery (PMID:12446666)
• Oncogenomic recombination hotspot around the PPP1R1B-STARD3-TCAP-PNMT-PERLD1-ERBB2-C17orf37-GRB7 amplicon at human chromosome 17q12 is closely linked to evolutionary recombination hotspot around the GSDML-GSDM locus. (PMID:15010812)
• TCAP mutations identified which are associated with hypertrophic cardiomyopathy. (PMID:15582318)
• The titin Z1Z2-telethonin complex resist considerable mechanical force through beta strand crosslinking, suggesting that telethonin is an important component of the N-terminal titin anchor. (PMID:16531234)
• A dimer of two titin/telethonin complexes is formed within the crystal environment, potentially indicating the formation of higher oligomers. (PMID:16713295)
• Hypertension induced expression of prohypertrophic BMP10, and the hypertrophic effect of BMP10 was modulated, at least in part, by its binding to Tcap at the Z disc. (PMID:17921333)
• telethonin is a sodium channel-interacting protein, and its mutations can alter Na(v)1.5 kinetics and may play a role in intestinal pseudo-obstruction (PMID:18408010)
• Telethonin might be involved in CVB3-mediated cell damage and in the resulting cardiac dysfunction due to the interaction with Siva. (PMID:18849585)
• Genetic studies of tcap in zebrafish suggested that pathogenesis in LGMD2G is due to a disruption of sarcomere-T-tubular interaction, but not of sarcomere assembly per se. (PMID:19679566)
• reduced expression of dystrophin and titin is associated with the pathophysiology of dilated cardiomyopathy, and TNF-alpha may modulate the expression of these proteins via NF-kappaB pathway. (PMID:20373002)
• This study identified no pathogenic mutations in BAG3, MATR3, PTRF or TCAP in Australian muscular dystrophy. (PMID:21683594)
• Report TCAP mutations in dilated cardiomyopathy. (PMID:24037902)
• cardiac telethonin is constitutively bis-phosphorylated and suggest that such phosphorylation is critical for normal telethonin function, which may include maintenance of transverse tubule organization and intracellular Ca(2+) transients. (PMID:24280220)
• Data indicate LGMD2G protein TCAP association with limb girdle muscular dystrophy 2G (LGMD2G). (PMID:25055047)
• based on the crystal structure in which Z1Z2 and telethonin1-90 assemble into a 2:1 complex, a single chain fusion protein was designed, comprising two Z1Z2 modules that are connected by flexible linkers N- and C-terminally of the telethonin1-90. Expression of this fusion protein, named ZTZ, affords high yields of soluble expressed and purified protein (PMID:28811266)
• limb-girdle muscular dystrophy type 2G appears to be a common form among Bulgarian Muslims. Homozygosity for c.75G>A, p.Trp25X is associated with a homogeneous clinical presentation, but the clinical course and severity of the disease show inter- and intra-familial variation. (PMID:29935994)
• Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy. (PMID:32565061)
• Telethonin variants found in Brugada syndrome, J-wave pattern ECG, and ARVC reduce peak Nav 1.5 currents in HEK-293 cells. (PMID:32588437)
• Distal myopathy due to TCAP variants in four unrelated Chinese patients. (PMID:32761539)
• The clinical features and TCAP mutation spectrum in a Chinese cohort of patients with limb-girdle muscular dystrophy R7. (PMID:37216648)
• TCAP gene is not a common cause of cardiomyopathy in Iranian patients. (PMID:37752589)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tcap	ENSDARG00000007344
mus_musculus	Tcap	ENSMUSG00000007877
rattus_norvegicus	Tcap	ENSRNOG00000068106

Protein

Protein identifiers

Telethonin — O15273 (reviewed: O15273)

Alternative names: Titin cap protein

All UniProt accessions (3): O15273, A2TDC0, J3KT40

UniProt curated annotations — full annotation on UniProt →

Function. Muscle assembly regulating factor. Mediates the antiparallel assembly of titin (TTN) molecules at the sarcomeric Z-disk.

Subunit / interactions. Interacts with MYOZ1, MYOZ2 and MYOZ3. Interacts with CSRP3. Interacts directly with the N-terminal Ig-like domains of 2 titin (TTN) molecules. Interacts with ANKRD2; the interaction is direct.

Subcellular location. Cytoplasm. Myofibril. Sarcomere.

Tissue specificity. Heart and skeletal muscle.

Disease relevance. Cardiomyopathy, familial hypertrophic, 25 (CMH25) [MIM:607487] A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. The disease is caused by variants affecting the gene represented in this entry. Muscular dystrophy, limb-girdle, autosomal recessive 7 (LGMDR7) [MIM:601954] An autosomal recessive degenerative myopathy characterized by proximal and distal muscle weakness and atrophy in the limbs, dystrophic changes on muscle biopsy, and absence of telethonin. Cardiac muscle is involved in a subset of patients. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. The C-terminal domain appears to be unstructured in solution. It may promote the assembly of higher-order TTN complexes.

RefSeq proteins (1): NP_003664* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015667	Telethonin	Family
IPR023111	Titin-like_dom_sf	Homologous_superfamily

Pfam: PF09470

UniProt features (23 total): sequence variant 9, strand 7, turn 2, chain 1, region of interest 1, helix 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1YA5	X-RAY DIFFRACTION	2.44
2F8V	X-RAY DIFFRACTION	2.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15273-F1	79.89	0.49

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): 39

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-390522	Striated Muscle Contraction
R-HSA-397014	Muscle contraction

MSigDB gene sets: 248 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_RESPONSE_TO_MUSCLE_STRETCH, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_OTIC_VESICLE_DEVELOPMENT, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GOBP_CARDIAC_MYOFIBRIL_ASSEMBLY, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT, GOBP_SARCOMERE_ORGANIZATION, GOBP_SKELETAL_MUSCLE_CONTRACTION, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_DETECTION_OF_MECHANICAL_STIMULUS

GO Biological Process (22): somitogenesis (GO:0001756), skeletal muscle contraction (GO:0003009), cardiac muscle hypertrophy (GO:0003300), adult heart development (GO:0007512), cardiac muscle hypertrophy in response to stress (GO:0014898), muscle filament sliding (GO:0030049), skeletal muscle thin filament assembly (GO:0030240), skeletal muscle myosin thick filament assembly (GO:0030241), otic vesicle formation (GO:0030916), response to muscle stretch (GO:0035994), detection of muscle stretch (GO:0035995), sarcomere organization (GO:0045214), sarcomerogenesis (GO:0048769), detection of mechanical stimulus (GO:0050982), cardiac myofibril assembly (GO:0055003), cardiac muscle tissue morphogenesis (GO:0055008), cardiac muscle cell development (GO:0055013), cardiac muscle contraction (GO:0060048), protein-containing complex assembly (GO:0065003), animal organ morphogenesis (GO:0009887), anatomical structure formation involved in morphogenesis (GO:0048646), tissue morphogenesis (GO:0048729)

GO Molecular Function (9): structural constituent of muscle (GO:0008307), protein-macromolecule adaptor activity (GO:0030674), titin binding (GO:0031432), BMP binding (GO:0036122), transmembrane transporter binding (GO:0044325), FATZ binding (GO:0051373), molecular adaptor activity (GO:0060090), titin Z domain binding (GO:0070080), protein binding (GO:0005515)

GO Cellular Component (6): cytosol (GO:0005829), Z disc (GO:0030018), I band (GO:0031674), titin-telethonin complex (GO:1990733), cytoplasm (GO:0005737), sarcomere (GO:0030017)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
myofibril assembly	3
striated muscle contraction	2
skeletal myofibril assembly	2
response to mechanical stimulus	2
actomyosin structure organization	2
protein binding	2
cytoskeletal protein binding	2
binding	2
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
musculoskeletal movement	1
striated muscle hypertrophy	1
heart development	1
muscle hypertrophy in response to stress	1
cardiac muscle hypertrophy	1
cardiac muscle adaptation	1
muscle contraction	1
actin-myosin filament sliding	1
actin filament organization	1
striated muscle myosin thick filament assembly	1
otic vesicle morphogenesis	1
epithelial tube formation	1
response to muscle stretch	1
detection of mechanical stimulus	1
detection of external stimulus	1
detection of abiotic stimulus	1
cardiac muscle cell development	1
heart morphogenesis	1
cardiac muscle tissue development	1
muscle tissue morphogenesis	1
striated muscle cell development	1
cardiac cell development	1
cardiac muscle cell differentiation	1
heart contraction	1
cellular component assembly	1
protein-containing complex organization	1

Protein interactions and networks

STRING

1162 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCAP	TTN	Q8WZ42	999
TCAP	CSRP3	P50461	996
TCAP	MYOZ2	Q9NPC6	975
TCAP	MYOZ1	Q9NP98	958
TCAP	ANKRD2	Q9GZV1	908
TCAP	MYH7	P12883	907
TCAP	ACTN2	P35609	899
TCAP	FLNC	Q14315	875
TCAP	LDB3	O75112	868
TCAP	TRIM63	Q969Q1	864
TCAP	MYBPC3	Q14896	862
TCAP	MYOT	Q9UBF9	861
TCAP	CAPN3	P20807	843
TCAP	OBSCN	Q5VST9	821
TCAP	FKTN	O75072	816

IntAct

172 interactions, top by confidence:

A	B	Type	Score
TTN	TCAP	psi-mi:“MI:0407”(direct interaction)	0.860
TTN	TCAP	psi-mi:“MI:0915”(physical association)	0.860
TCAP	TTN	psi-mi:“MI:0915”(physical association)	0.860
TCAP	CBX5	psi-mi:“MI:0915”(physical association)	0.740
TCAP	ATXN1	psi-mi:“MI:0915”(physical association)	0.740
LAMTOR5	TCAP	psi-mi:“MI:0915”(physical association)	0.670
TCAP	TTC19	psi-mi:“MI:0915”(physical association)	0.670
TCAP	HSPA8	psi-mi:“MI:0914”(association)	0.660
CSRP3	TCAP	psi-mi:“MI:0915”(physical association)	0.630
CSRP3	TCAP	psi-mi:“MI:0914”(association)	0.630
CETN3	TCAP	psi-mi:“MI:0915”(physical association)	0.590
TTN	TCAP	psi-mi:“MI:0407”(direct interaction)	0.560
TCAP	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
TCAP	PLEKHF2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (80): TCAP (Two-hybrid), TCAP (Two-hybrid), TCAP (Two-hybrid), SIVA1 (Reconstituted Complex), TCAP (Two-hybrid), TCAP (Two-hybrid), LHX4 (Two-hybrid), TTN (Two-hybrid), CBX5 (Affinity Capture-MS), TCAP (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), STUB1 (Affinity Capture-MS), HSPA4 (Affinity Capture-MS), ANKRD2 (Affinity Capture-Western), TCAP (Reconstituted Complex)

ESM2 similar proteins: A0A1B0GTK4, A6NLE4, A8K554, F1MQW7, J3QMY9, O15273, O70548, O70552, P03246, P03247, P05857, P0DJZ2, P0DL12, P11305, P14254, P17758, P18097, P18801, P20919, P22378, P32543, P47939, P47940, P57738, Q0VD86, Q1X700, Q1X711, Q3TTJ4, Q5R7E2, Q5W5W9, Q61312, Q66669, Q66HF0, Q6GVM5, Q6UYE1, Q7L4S7, Q80VY2, Q86WR6, Q8K3A6, Q8N6T0

Diamond homologs: O15273, O70548, Q6T8D8

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
GSK3B	“down-regulates quantity by destabilization”	TCAP	phosphorylation
FBXL21P	“down-regulates quantity by destabilization”	TCAP	ubiquitination
TCAP	“up-regulates activity”	TTN	binding
TCAP	“up-regulates activity”	Sarcomere_organization	binding
TTN	unknown	TCAP	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	13
Uncertain significance	213
Likely benign	101
Benign	7

Top pathogenic / likely-pathogenic (29)

Variant ID	HGVS	Classification
1055526	NM_003673.4(TCAP):c.110+5G>A	Pathogenic
1382475	NM_003673.4(TCAP):c.166C>T (p.Gln56Ter)	Pathogenic
1459213	NM_003673.4(TCAP):c.34del (p.Glu12fs)	Pathogenic
189787	NM_003673.4(TCAP):c.410C>T (p.Thr137Ile)	Pathogenic
2023376	NM_003673.4(TCAP):c.110+2T>C	Pathogenic
2065429	NM_003673.4(TCAP):c.45_46del (p.Cys15_Glu16delinsTer)	Pathogenic
2090126	NM_003673.4(TCAP):c.151_154del (p.Tyr51fs)	Pathogenic
286261	NM_003673.4(TCAP):c.103G>T (p.Glu35Ter)	Pathogenic
2948047	NM_003673.4(TCAP):c.50_51dup (p.Arg18fs)	Pathogenic
3223539	NM_003673.4(TCAP):c.25G>T (p.Glu9Ter)	Pathogenic
3757356	NM_003673.4(TCAP):c.154dup (p.His52fs)	Pathogenic
3804984	NM_003673.4(TCAP):c.215del (p.Gly72fs)	Pathogenic
448649	NM_003673.4(TCAP):c.26_33dup (p.Glu12fs)	Pathogenic
4789023	NM_003673.4(TCAP):c.152_153insAA (p.Tyr51Ter)	Pathogenic
5526	NM_003673.4(TCAP):c.110_110+1del	Pathogenic
835598	NM_003673.4(TCAP):c.136_137del (p.Gln46fs)	Pathogenic
1066432	NM_003673.4(TCAP):c.171C>A (p.Cys57Ter)	Likely pathogenic
1180772	NM_003673.4(TCAP):c.14_15del (p.Glu5fs)	Likely pathogenic
140582	NM_003673.4(TCAP):c.32C>A (p.Ser11Ter)	Likely pathogenic
1687576	NM_003673.4(TCAP):c.110+1G>A	Likely pathogenic
1708038	NM_003673.4(TCAP):c.360_361del (p.Glu120fs)	Likely pathogenic
202113	NM_003673.4(TCAP):c.110+5G>T	Likely pathogenic
217014	NM_003673.4(TCAP):c.25_31dup (p.Ser11Ter)	Likely pathogenic
2562755	NM_003673.4(TCAP):c.110_110+1dup	Likely pathogenic
2647720	NM_003673.4(TCAP):c.410_411del (p.Thr137fs)	Likely pathogenic
3752172	NM_003673.4(TCAP):c.1A>T (p.Met1Leu)	Likely pathogenic
3897040	NM_003673.4(TCAP):c.110+1_110+5del	Likely pathogenic
4073562	NM_003673.4(TCAP):c.165del (p.Gln56fs)	Likely pathogenic
587470	NM_003673.4(TCAP):c.1A>G (p.Met1Val)	Likely pathogenic

SpliceAI

169 predictions. Top by Δscore:

Variant	Effect	Δscore
17:39665714:A:AG	acceptor_gain	1.0000
17:39665714:AGCT:A	acceptor_gain	1.0000
17:39665715:G:GA	acceptor_gain	1.0000
17:39665715:GCT:G	acceptor_gain	1.0000
17:39665715:GCTG:G	acceptor_gain	1.0000
17:39665712:CCAGC:C	acceptor_loss	0.9900
17:39665713:CAG:C	acceptor_loss	0.9900
17:39665714:A:AC	acceptor_loss	0.9900
17:39665715:GC:G	acceptor_gain	0.9900
17:39665715:GCTGC:G	acceptor_gain	0.9900
17:39665717:T:A	acceptor_gain	0.9800
17:39665372:G:C	acceptor_gain	0.9600
17:39665467:GGG:G	donor_gain	0.9200
17:39665468:GGG:G	donor_gain	0.9200
17:39665372:GAGCT:G	acceptor_gain	0.8400
17:39665434:G:GT	donor_gain	0.8300
17:39665468:GG:G	donor_gain	0.8300
17:39665469:GG:G	donor_gain	0.8300
17:39665371:A:AG	acceptor_gain	0.8200
17:39665372:G:GG	acceptor_gain	0.8200
17:39665470:G:GG	donor_gain	0.8200
17:39665465:GAGGG:G	donor_gain	0.7800
17:39665466:AGGGG:A	donor_loss	0.7400
17:39665469:GGTG:G	donor_loss	0.7400
17:39665470:G:GT	donor_loss	0.7400
17:39665471:T:A	donor_loss	0.7400
17:39665472:GA:G	donor_loss	0.7400
17:39665473:AGTG:A	donor_loss	0.7400
17:39665474:G:C	donor_loss	0.7300
17:39665376:T:A	acceptor_gain	0.7100

AlphaMissense

1065 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:39665432:T:A	W25R	0.978
17:39665432:T:C	W25R	0.978
17:39665885:T:C	F94L	0.978
17:39665887:C:A	F94L	0.978
17:39665887:C:G	F94L	0.978
17:39665434:G:C	W25C	0.972
17:39665434:G:T	W25C	0.972
17:39665420:T:C	F21L	0.969
17:39665422:C:A	F21L	0.969
17:39665422:C:G	F21L	0.969
17:39665426:G:C	A23P	0.951
17:39665819:G:C	G72R	0.944
17:39665442:T:C	L28P	0.937
17:39665886:T:C	F94S	0.936
17:39665433:G:C	W25S	0.918
17:39665433:G:T	W25L	0.904
17:39666012:T:C	I136T	0.902
17:39665814:G:C	R70P	0.900
17:39665438:G:C	D27H	0.897
17:39665820:G:T	G72V	0.882
17:39666103:A:C	R166S	0.880
17:39666103:A:T	R166S	0.880
17:39665883:T:C	I93T	0.874
17:39665440:T:A	D27E	0.871
17:39665440:T:G	D27E	0.871
17:39665790:A:C	Q62P	0.871
17:39666104:G:C	G167R	0.870
17:39665886:T:G	F94C	0.869
17:39665883:T:A	I93N	0.867
17:39665846:T:G	Y81D	0.865

dbSNP variants (sampled 300 via entrez): RS1000303052 (17:39666412 C>T), RS1002246079 (17:39663745 GTC>G), RS1003680419 (17:39663496 C>G), RS1004534829 (17:39664459 A>G), RS1005110598 (17:39664632 G>T), RS1006207916 (17:39665614 C>A,T), RS1007111530 (17:39666989 A>AC), RS1008753988 (17:39666234 G>A,C,T), RS1009731149 (17:39664964 G>A), RS1009783137 (17:39665135 A>G), RS1010794675 (17:39666194 G>T), RS1010917945 (17:39663965 C>T), RS1011013010 (17:39663830 C>G), RS1012238051 (17:39663537 A>C), RS1012705096 (17:39663808 C>T)

Disease associations

OMIM: gene MIM:604488 | disease phenotypes: MIM:607487, MIM:192600, MIM:601954, MIM:601144, MIM:194200, MIM:115197

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive limb-girdle muscular dystrophy type 2G	Strong	Autosomal recessive
hypertrophic cardiomyopathy 25	Strong	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
hypertrophic cardiomyopathy	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
dilated cardiomyopathy	Limited	AD
hypertrophic cardiomyopathy	Disputed	AD
autosomal recessive limb-girdle muscular dystrophy	Definitive	AR

Mondo (13): hypertrophic cardiomyopathy 25 (MONDO:0011843), familial hypertrophic cardiomyopathy (MONDO:0024573), autosomal recessive limb-girdle muscular dystrophy type 2G (MONDO:0011170), dilated cardiomyopathy (MONDO:0005021), cardiomyopathy (MONDO:0004994), hypertrophic cardiomyopathy (MONDO:0005045), Brugada syndrome (MONDO:0015263), hypertrophic cardiomyopathy 1 (MONDO:0008647), ventricular tachycardia (MONDO:0005477), Wolff-Parkinson-White syndrome (MONDO:0008685), long QT syndrome (MONDO:0002442), hypertrophic cardiomyopathy 4 (MONDO:0007268), (MONDO:0015470)

Orphanet (8): Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Telethonin-related limb-girdle muscular dystrophy R7 (Orphanet:34514), Dilated cardiomyopathy (Orphanet:217604), Rare cardiomyopathy (Orphanet:167848), Rare hypertrophic cardiomyopathy (Orphanet:217569), Brugada syndrome (Orphanet:130), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001288	Gait disturbance
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001712	Left ventricular hypertrophy
HP:0001716	Wolff-Parkinson-White syndrome
HP:0001727	Thromboembolic stroke
HP:0002522	Areflexia of lower limbs
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003457	EMG abnormality
HP:0003551	Difficulty climbing stairs
HP:0003557	Increased variability in muscle fiber diameter
HP:0003560	Muscular dystrophy
HP:0003581	Adult onset
HP:0003805	Rimmed vacuoles
HP:0008944	Distal lower limb amyotrophy
HP:0008948	Proximal upper limb amyotrophy
HP:0008981	Calf muscle hypertrophy
HP:0008994	Proximal lower limb muscle weakness
HP:0008997	Proximal upper limb muscle weakness
HP:0009025	Increased connective tissue
HP:0009027	Foot dorsiflexor weakness
HP:0009046	Difficulty running
HP:0009053	Distal lower limb muscle weakness

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000624_15	Ulcerative colitis	3.000000e-08
GCST007235_3	Pancreatic ductal adenocarcinoma	1.000000e-06
GCST007564_21	Asthma or allergic disease (pleiotropy)	4.000000e-17
GCST008757_30	Alcohol consumption	1.000000e-09
GCST008916_10	Asthma	5.000000e-09
GCST008916_21	Asthma	2.000000e-62
GCST008916_45	Asthma	3.000000e-10
GCST008916_86	Asthma	2.000000e-14
GCST009798_16	Asthma	8.000000e-27
GCST010002_123	Refractive error	1.000000e-24

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C564388	Cardiomyopathy, Dilated, 1N (supp.)
C566169	Cardiomyopathy, Familial Hypertrophic, 4 (supp.)
C566599	Muscular Dystrophy, Limb-Girdle, Type 2G (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression	3
Tobacco Smoke Pollution	increases expression	2
Triclosan	decreases expression	2
aristolochic acid I	increases expression	1
testosterone enanthate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tris(2-butoxyethyl) phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2,7-dihydroxynaphthalene	decreases expression	1
2-palmitoylglycerol	increases expression	1
licochalcone B	increases expression	1
jinfukang	decreases expression	1
MT19c compound	decreases expression	1
Sunitinib	decreases expression	1
Glyphosate	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Etoposide	decreases expression	1
Smoke	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
2,4-Dichlorophenoxyacetic Acid	increases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy