FHOD3

Summary

FHOD3 (formin homology 2 domain containing 3, HGNC:26178) is a protein-coding gene on chromosome 18q12.2, encoding FH1/FH2 domain-containing protein 3 (Q2V2M9). Actin-organizing protein that may cause stress fiber formation together with cell elongation.

The protein encoded by this gene is a member of the diaphanous-related formins (DRF), and contains multiple domains, including GBD (GTPase-binding domain), DID (diaphanous inhibitory domain), FH1 (formin homology 1), FH2 (formin homology 2), and DAD (diaphanous auto-regulatory domain) domains. This protein is thought to play a role in actin filament polymerization in cardiomyocytes. Mutations in this gene have been associated with dilated cardiomyopathy (DCM), characterized by dilation of the ventricular chamber, leading to impairment of systolic pump function and subsequent heart failure. Increased levels of the protein encoded by this gene have been observed in individuals with hypertrophic cardiomyopathy (HCM). Alternative splicing results in multiple transcript variants encoding different isoforms. A muscle-specific isoform has been shown to possess a casein kinase 2 (CK2) phosphorylation site at the C-terminal end of the FH2 domain. Phosphorylation of this site alters its interaction with sequestosome 1 (SQSTM1), and targets this isoform to myofibrils, while other isoforms form cytoplasmic aggregates.

Source: NCBI Gene 80206 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertrophic cardiomyopathy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 25
• Clinical variants (ClinVar): 503 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 13
• MANE Select transcript: NM_001281740

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26178
Approved symbol	FHOD3
Name	formin homology 2 domain containing 3
Location	18q12.2
Locus type	gene with protein product
Status	Approved
Aliases	FHOS2, KIAA1695, FLJ22297, FLJ22717
Ensembl gene	ENSG00000134775
Ensembl biotype	protein_coding
OMIM	609691
Entrez	80206

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 25 protein_coding, 2 retained_intron

ENST00000257209, ENST00000359247, ENST00000585579, ENST00000587493, ENST00000589114, ENST00000590592, ENST00000591635, ENST00000592128, ENST00000592930, ENST00000863104, ENST00000863105, ENST00000863106, ENST00000863107, ENST00000863108, ENST00000863109, ENST00000863110, ENST00000863111, ENST00000863112, ENST00000863113, ENST00000863114, ENST00000863115, ENST00000863116, ENST00000863117, ENST00000863118, ENST00000863119, ENST00000957407, ENST00000957408

RefSeq mRNA: 3 — MANE Select: NM_001281740 NM_001281739, NM_001281740, NM_025135

CCDS: CCDS32816, CCDS62418, CCDS62419

Canonical transcript exons

ENST00000590592 — 29 exons

Exon	Start	End
ENSE00000916123	36742737	36742856
ENSE00000916124	36744032	36744193
ENSE00000916125	36746945	36747135
ENSE00000916126	36755119	36755311
ENSE00000916127	36760608	36760782
ENSE00000948418	36687128	36687178
ENSE00001269587	36717832	36718715
ENSE00002743841	36779448	36780220
ENSE00002755070	36652570	36652929
ENSE00002810303	36653342	36653416
ENSE00002954260	36649316	36649405
ENSE00002969683	36759118	36759141
ENSE00003459036	36602674	36602768
ENSE00003463608	36512438	36512543
ENSE00003481013	36611952	36612095
ENSE00003513938	36709095	36709391
ENSE00003537006	36769265	36769426
ENSE00003555969	36576451	36576545
ENSE00003593416	36693209	36693423
ENSE00003595391	36594787	36594898
ENSE00003611513	36372680	36372744
ENSE00003628886	36625511	36625749
ENSE00003632622	36501932	36501999
ENSE00003651682	36355539	36355645
ENSE00003662847	36658075	36658188
ENSE00003692967	36681436	36681570
ENSE00003713701	36730646	36730804
ENSE00003722930	36740656	36740838
ENSE00003926291	36297713	36298000

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 98.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.7699 / max 408.4610, expressed in 1192 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169964	11.2102	1162
169976	0.4917	162
169963	0.4146	207
169973	0.1653	81
169974	0.1474	76
169975	0.1110	66
169977	0.0755	18
169972	0.0579	24
169968	0.0512	8
169967	0.0228	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.47	gold quality
left ventricle myocardium	UBERON:0006566	97.79	gold quality
ventricular zone	UBERON:0003053	97.62	gold quality
heart left ventricle	UBERON:0002084	97.60	gold quality
cardiac ventricle	UBERON:0002082	97.55	gold quality
heart right ventricle	UBERON:0002080	96.08	gold quality
right atrium auricular region	UBERON:0006631	95.76	gold quality
cardiac atrium	UBERON:0002081	95.54	gold quality
heart	UBERON:0000948	95.23	gold quality
mucosa of stomach	UBERON:0001199	94.43	gold quality
ganglionic eminence	UBERON:0004023	94.13	gold quality
myocardium	UBERON:0002349	93.97	gold quality
oocyte	CL:0000023	93.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.58	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.63	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.45	gold quality
gluteal muscle	UBERON:0002000	92.28	gold quality
pons	UBERON:0000988	91.92	gold quality
corpus epididymis	UBERON:0004359	91.31	gold quality
cortical plate	UBERON:0005343	90.99	gold quality
right adrenal gland	UBERON:0001233	90.80	gold quality
left adrenal gland	UBERON:0001234	90.20	gold quality
right adrenal gland cortex	UBERON:0035827	90.06	gold quality
muscle of leg	UBERON:0001383	90.02	gold quality
seminal vesicle	UBERON:0000998	89.92	gold quality
left adrenal gland cortex	UBERON:0035825	89.76	gold quality
gastrocnemius	UBERON:0001388	89.53	gold quality
muscle organ	UBERON:0001630	89.47	gold quality
skeletal muscle organ	UBERON:0014892	89.46	gold quality
secondary oocyte	CL:0000655	89.30	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	51.99
E-GEOD-81608	yes	4.89
E-ANND-3	no	6.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting FHOD3, 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-4668-3P	100.00	68.74	2635
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-568	99.98	69.86	2084
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-5008-3P	98.73	67.50	1433
HSA-MIR-216B-3P	98.55	67.19	1223

Literature-anchored findings (GeneRIF, showing 15)

• Single nucleotide polymorphism in FHOD3 gene is associated with acute lymphoblastic leukemia. (PMID:19066393)
• actin dynamics regulated by Fhod3 are critical for sarcomere organization in striated muscle cells. (PMID:19706596)
• C-terminal phosphorylation by ROCK1 is sufficient for FHOD3 activation as evidenced by an increase in F-actin in HeLa cells. (PMID:23052206)
• FHOD variants is with hypertrophic cardiomyopathy. (PMID:23255317)
• DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly. (PMID:24088304)
• Suggest alpha5beta1/Arp2/Arp3/FHOD3 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo. (PMID:26370503)
• FHOD3 played a role in glioma linear migration. (PMID:26912794)
• FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 2% of cases. (PMID:30442288)
• These results indicate that RBM20 and PTBP1 play a role in the actin filament functional organization mediated by FHOD3 isoforms and suggest their possible involvement in heart diseases. (PMID:30468920)
• Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy. (PMID:31742804)
• Deletions of specific exons of FHOD3 detected by next-generation sequencing are associated with hypertrophic cardiomyopathy. (PMID:32335906)
• FHOD3 promotes carcinogenesis by regulating RhoA/ROCK1/LIMK1 signaling pathway in medulloblastoma. (PMID:32447646)
• Variant Spectrum of Formin Homology 2 Domain-Containing 3 Gene in Chinese Patients With Hypertrophic Cardiomyopathy. (PMID:33586461)
• A novel splice-site FHOD3 founder variant is a common cause of hypertrophic cardiomyopathy in the population of the Balkans-A cohort study. (PMID:38051749)
• Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers. (PMID:38160043)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fhod3	ENSMUSG00000034295
rattus_norvegicus	Fhod3	ENSRNOG00000027230
caenorhabditis_elegans		WBGENE00018976

Paralogs (18): DAAM1 (ENSG00000100592), FNBP4 (ENSG00000109920), DIAPH1 (ENSG00000131504), FHOD1 (ENSG00000135723), FHDC1 (ENSG00000137460), DIAPH3 (ENSG00000139734), DAAM2 (ENSG00000146122), DIAPH2 (ENSG00000147202), FMN2 (ENSG00000155816), FMNL2 (ENSG00000157827), FMNL3 (ENSG00000161791), FMNL1 (ENSG00000184922), FAM47A (ENSG00000185448), SHTN1 (ENSG00000187164), FAM47B (ENSG00000189132), FAM47C (ENSG00000198173), INF2 (ENSG00000203485), GRID2IP (ENSG00000215045)

Protein

Protein identifiers

FH1/FH2 domain-containing protein 3 — Q2V2M9 (reviewed: Q2V2M9)

Alternative names: Formactin-2, Formin homolog overexpressed in spleen 2

All UniProt accessions (5): A0A0A0MTS9, Q2V2M9, K7EKZ0, K7EP24, K7ER94

UniProt curated annotations — full annotation on UniProt →

Function. Actin-organizing protein that may cause stress fiber formation together with cell elongation. Isoform 4 may play a role in actin filament polymerization in cardiomyocytes.

Subunit / interactions. Interacts with nestin/NES-based interfilament (IF). Interacts with SQSTM1; isoform 4 threonine phosphorylation disrupts SQSTM1-binding.

Subcellular location. Cytoplasm. Cytoskeleton Cytoplasm. Myofibril. Sarcomere. Z line.

Tissue specificity. Expressed in the heart, kidney and brain. May be down-regulated in various types of heart diseases, including idiopathic dilated, ventricular dilated, familial dilated and perinatal dilated cardiomyopathies, as well as ischemic heart disease (at protein level).

Post-translational modifications. Phosphorylated on Thr-1474 and Thr-1476 by CK2.

Disease relevance. Cardiomyopathy, familial hypertrophic, 28 (CMH28) [MIM:619402] A form of hypertrophic cardiomyopathy, a 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. CMH28 is an autosomal dominant form with incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments.

Similarity. Belongs to the formin homology family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q2V2M9-1	1	yes
Q2V2M9-2	2
Q2V2M9-3	3
Q2V2M9-4	4

RefSeq proteins (3): NP_001268668, NP_001268669, NP_079411 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR014767	DAD_dom	Domain
IPR014768	GBD/FH3_dom	Domain
IPR015425	FH2_Formin	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR041387	FHOD1_GBD_N	Domain
IPR042201	FH2_Formin_sf	Homologous_superfamily
IPR056771	FH3_FHOD1-3-like	Domain

Pfam: PF02181, PF18382, PF24959

UniProt features (77 total): sequence variant 28, compositionally biased region 15, sequence conflict 10, region of interest 8, modified residue 6, domain 4, splice variant 4, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2V2M9-F1	64.62	0.26

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 (6): 345, 375, 763, 775, 1474, 1476

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 197 (showing top): GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, JAEGER_METASTASIS_DN, BOYAULT_LIVER_CANCER_SUBCLASS_G2, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_CARDIAC_MYOFIBRIL_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_SARCOMERE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CHANDRAN_METASTASIS_DN, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, RODRIGUES_NTN1_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, chr18q12, GOBP_CELLULAR_COMPONENT_ASSEMBLY_INVOLVED_IN_MORPHOGENESIS

GO Biological Process (4): actin filament organization (GO:0007015), sarcomere organization (GO:0045214), positive regulation of stress fiber assembly (GO:0051496), cardiac myofibril assembly (GO:0055003)

GO Molecular Function (3): actin filament binding (GO:0051015), actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), cytoskeleton (GO:0005856), Z disc (GO:0030018)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
myofibril assembly	2
cellular anatomical structure	2
actin cytoskeleton organization	1
supramolecular fiber organization	1
actomyosin structure organization	1
positive regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
cardiac muscle cell development	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
binding	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
I band	1

Protein interactions and networks

STRING

380 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FHOD3	DES	P17661	761
FHOD3	NES	P48681	650
FHOD3	STRN3	Q13033	556
FHOD3	GFAP	P14136	495
FHOD3	FMNL3	Q8IVF7	467
FHOD3	FMN1	Q68DA7	394
FHOD3	TTN	Q8WZ42	378
FHOD3	PFN4	Q8NHR9	377
FHOD3	RBM20	Q5T481	368
FHOD3	TTC22	Q5TAA0	349
FHOD3	STAB1	Q9NY15	348
FHOD3	DAAM2	Q86T65	347
FHOD3	STRIP2	Q9ULQ0	346
FHOD3	FHDC1	Q9C0D6	339
FHOD3	GLB1L3	Q8NCI6	324

IntAct

12 interactions, top by confidence:

A	B	Type	Score
CDC16	BUB1B	psi-mi:“MI:0914”(association)	0.790
CDC23	BUB1B	psi-mi:“MI:0914”(association)	0.790
FHOD3	SQSTM1	psi-mi:“MI:0915”(physical association)	0.540
SQSTM1	FHOD3	psi-mi:“MI:0915”(physical association)	0.540
SQSTM1	FHOD3	psi-mi:“MI:0403”(colocalization)	0.540
FHOD3	SQSTM1	psi-mi:“MI:0403”(colocalization)	0.540
FHOD3	IKBIP	psi-mi:“MI:0915”(physical association)	0.400
ANAPC4	BUB1	psi-mi:“MI:0914”(association)	0.350
FHOD3	Sqstm1	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (15): FHOD3 (Affinity Capture-MS), FHOD3 (Affinity Capture-MS), IKBIP (Proximity Label-MS), FHOD3 (Affinity Capture-MS), FHOD3 (Affinity Capture-MS), FHOD3 (Affinity Capture-MS), FHOD3 (Affinity Capture-MS), C1orf131 (Cross-Linking-MS (XL-MS)), FHOD3 (Cross-Linking-MS (XL-MS)), FHOD3 (Affinity Capture-MS), FHOD3 (Proximity Label-MS), FHOD3 (Proximity Label-MS), FHOD3 (Affinity Capture-Western), FHOD3 (Two-hybrid), SQSTM1 (Affinity Capture-Western)

ESM2 similar proteins: A0A8I3NFE2, A0FI79, B1AVH7, B5DFA1, D2H0G5, D7PF45, O00750, O15357, O70143, P29353, P97573, P98083, Q00IB7, Q0IIE2, Q15678, Q16825, Q17R13, Q2I6J0, Q2I6J1, Q2V2M9, Q5JV73, Q5M824, Q5R7W7, Q5U2X5, Q61120, Q62130, Q62136, Q62728, Q62925, Q69Z98, Q6P4S2, Q6P549, Q80TI1, Q8AY68, Q8BMC3, Q8BYW1, Q8IWQ3, Q8K245, Q92529, Q92835

Diamond homologs: A2XUA1, A2YVG8, A3AB67, O04532, O22824, O23373, O48682, Q0D519, Q0D5P3, Q0DLG0, Q10Q99, Q2V2M9, Q54ER5, Q69MT2, Q6H7U3, Q6MWG9, Q6ZKB2, Q76LL6, Q7XUV2, Q7XWS7, Q8GX37, Q8H8K7, Q8S0F0, Q94B77, Q9FJX6, Q9FLQ7, Q9MA60, Q9SE97, Q9XIE0, Q9Z207, Q6P9Q4, Q9Y613

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CSNK2A1	down-regulates	FHOD3	phosphorylation
ROCK1	“up-regulates activity”	FHOD3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	280
Likely benign	70
Benign	102

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1174143	NM_001281740.3:c.1836-1527_2022-2042del	Pathogenic
58762	GRCh38/hg38 18q11.1-23(chr18:20989762-80209986)x3	Pathogenic
3065960	NM_001281740.3(FHOD3):c.4787-1G>A	Likely pathogenic
3894904	NM_001281740.3(FHOD3):c.1646G>A (p.Ser549Asn)	Likely pathogenic
3895408	NM_001281740.3(FHOD3):c.1646+1G>C	Likely pathogenic
4820098	NM_001281740.3(FHOD3):c.719-1G>T	Likely pathogenic

SpliceAI

6867 predictions. Top by Δscore:

Variant	Effect	Δscore
18:36298001:GTAC:G	donor_loss	1.0000
18:36298002:T:G	donor_loss	1.0000
18:36353648:GGTA:G	donor_gain	1.0000
18:36355641:GCCGG:G	donor_gain	1.0000
18:36355643:CGGGT:C	donor_loss	1.0000
18:36355644:GG:G	donor_gain	1.0000
18:36355644:GGGT:G	donor_loss	1.0000
18:36355645:GG:G	donor_gain	1.0000
18:36355645:GGTAA:G	donor_loss	1.0000
18:36355646:G:A	donor_loss	1.0000
18:36355646:G:GG	donor_gain	1.0000
18:36355647:T:G	donor_loss	1.0000
18:36501925:A:AG	acceptor_gain	1.0000
18:36501926:TTTCA:T	acceptor_loss	1.0000
18:36501927:TTCA:T	acceptor_loss	1.0000
18:36501928:TCAG:T	acceptor_loss	1.0000
18:36501929:CAGA:C	acceptor_loss	1.0000
18:36501930:A:AG	acceptor_gain	1.0000
18:36501931:G:GT	acceptor_gain	1.0000
18:36501931:GA:G	acceptor_gain	1.0000
18:36501931:GAA:G	acceptor_gain	1.0000
18:36501931:GAAA:G	acceptor_gain	1.0000
18:36501931:GAAAA:G	acceptor_gain	1.0000
18:36501996:TCAGG:T	donor_loss	1.0000
18:36501997:CAGG:C	donor_loss	1.0000
18:36501999:GG:G	donor_loss	1.0000
18:36502000:G:C	donor_loss	1.0000
18:36512541:GGG:G	donor_gain	1.0000
18:36512542:GGG:G	donor_gain	1.0000
18:36576446:TGTA:T	acceptor_loss	1.0000

AlphaMissense

10604 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:36512477:G:C	G149R	1.000
18:36718288:T:C	F805S	1.000
18:36718297:T:C	L808P	1.000
18:36718561:T:C	L896S	1.000
18:36718561:T:G	L896W	1.000
18:36718563:T:C	F897L	1.000
18:36718565:C:A	F897L	1.000
18:36718565:C:G	F897L	1.000
18:36718566:T:A	W898R	1.000
18:36718566:T:C	W898R	1.000
18:36718568:G:C	W898C	1.000
18:36718568:G:T	W898C	1.000
18:36730710:T:A	I969N	1.000
18:36730722:T:C	L973P	1.000
18:36730731:T:C	L976P	1.000
18:36730749:T:A	I982N	1.000
18:36730758:C:A	A985D	1.000
18:36740707:G:C	A1018P	1.000
18:36740753:T:C	F1033S	1.000
18:36740756:T:C	L1034P	1.000
18:36740765:T:C	L1037P	1.000
18:36740795:T:C	L1047P	1.000
18:36740801:T:C	L1049P	1.000
18:36740803:T:A	W1050R	1.000
18:36740803:T:C	W1050R	1.000
18:36742762:T:C	L1070P	1.000
18:36742770:G:A	G1073R	1.000
18:36742770:G:C	G1073R	1.000
18:36742822:T:C	L1090P	1.000
18:36742833:G:A	G1094R	1.000

dbSNP variants (sampled 300 via entrez): RS1000012229 (18:36580176 C>A), RS1000017632 (18:36497387 G>T), RS1000018527 (18:36374835 T>A,C), RS1000026261 (18:36483756 A>G), RS1000028051 (18:36542268 G>A), RS1000033003 (18:36357461 C>G), RS1000044393 (18:36494541 G>C), RS1000045903 (18:36705060 C>T), RS1000050004 (18:36397596 A>G), RS1000050450 (18:36696078 C>T), RS1000081106 (18:36541701 G>T), RS1000083557 (18:36547697 C>T), RS1000101428 (18:36583217 T>A), RS1000106159 (18:36358326 T>C), RS1000108528 (18:36500952 C>T)

Disease associations

OMIM: gene MIM:609691 | disease phenotypes: MIM:619402, MIM:619042, MIM:613690

GenCC curated gene-disease

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Definitive	Autosomal dominant
cardiomyopathy, familial hypertrophic, 28	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Definitive	AD

Mondo (6): cardiomyopathy, familial hypertrophic, 28 (MONDO:0030317), cardiomyopathy (MONDO:0004994), dilated cardiomyopathy (MONDO:0005021), hypertrophic cardiomyopathy (MONDO:0005045), spinal muscular atrophy, infantile, James type (MONDO:0033621), hypertrophic cardiomyopathy 7 (MONDO:0013369)

Orphanet (3): Rare cardiomyopathy (Orphanet:167848), Dilated cardiomyopathy (Orphanet:217604), Rare hypertrophic cardiomyopathy (Orphanet:217569)

HPO phenotypes

13 total (15 of 13 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001297	Stroke
HP:0001645	Sudden cardiac death
HP:0001670	Asymmetric septal hypertrophy
HP:0003581	Adult onset
HP:0005110	Atrial fibrillation
HP:0005157	Concentric hypertrophic cardiomyopathy
HP:0012664	Reduced left ventricular ejection fraction
HP:0031295	Left atrial enlargement
HP:0031656	Systolic anterior motion of the mitral valve
HP:0031992	Apical hypertrophic cardiomyopathy
HP:0032092	Left ventricular outflow tract obstruction
HP:4000004	Myocardial late gadolinium enhancement
HP:0001644	Dilated cardiomyopathy
HP:0001639	Hypertrophic cardiomyopathy

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000618_18	Response to antipsychotic treatment	1.000000e-07
GCST001762_99	Obesity-related traits	5.000000e-06
GCST002312_2	Periodontal disease-related phenotype (Socransky)	6.000000e-06
GCST003818_74	Resting heart rate	2.000000e-14
GCST003844_5	QRS duration	8.000000e-09
GCST005789_29	Resting heart rate	2.000000e-06
GCST006979_268	Heel bone mineral density	5.000000e-12
GCST007096_232	Pulse pressure	2.000000e-08
GCST007269_131	Pulse pressure	2.000000e-08
GCST008180_10	Spontaneous preterm birth with premature rupture of membranes	6.000000e-06
GCST008839_359	Height	5.000000e-07
GCST009028_59	Adverse response to drug	3.000000e-07
GCST010796_4581	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-23
GCST010796_4582	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-22
GCST010796_4583	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-17
GCST010796_4584	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-13
GCST010796_4585	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST011202_12	Dilated cardiomyopathy (MTAG)	4.000000e-09
GCST011205_10	Hypertrophic cardiomyopathy (MTAG)	2.000000e-21
GCST011210_6	Dilated cardiomyopathy	5.000000e-06
GCST011211_5	Hypertrophic cardiomyopathy	3.000000e-38
GCST012099_22	Hypertrophic cardiomyopathy (sarcomere negative)	3.000000e-25
GCST012099_23	Hypertrophic cardiomyopathy (sarcomere negative)	4.000000e-15
GCST012101_10	Hypertrophic cardiomyopathy	3.000000e-12
GCST012101_2	Hypertrophic cardiomyopathy	4.000000e-23

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004502	adiponectin measurement
EFO:0005054	QRS complex
EFO:0009270	heel bone mineral density
EFO:0005763	pulse pressure measurement
EFO:0006917	spontaneous preterm birth
EFO:0009658	adverse effect
EFO:0004327	electrocardiography

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression, increases expression	7
trichostatin A	affects cotreatment, decreases expression	3
Aflatoxin B1	decreases expression, decreases methylation, affects methylation	3
bisphenol A	affects methylation, affects cotreatment, decreases expression	2
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cisplatin	increases expression, decreases expression, affects cotreatment	2
Nickel	decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
methotrexate polyglutamate	affects abundance	1
beta-lapachone	decreases expression	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	affects methylation	1
glycidamide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dimethylarsinous acid	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

520 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
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
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy