MYH11

protein-coding

myosin heavy chain 11, the group of Myosin heavy chains, class II

Gene summary

The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]

MANE transcript

NM_002474.3

Inheritance

AR, AD

ClinVar variants

P:93U:1953B:1169

Top phenotype

Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr16:15,703,135-15,858,438

External References & Databases

Ensembl (ENSG00000133392)

Transcript & Mutation Effects

hg38 • Region Span ~155.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

megacystis-microcolon-intestinal hypoperistalsis syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0025708

Submitter: Labcorp Genetics (formerly Invitae)

megacystis-microcolon-intestinal hypoperistalsis syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007960

Submitter: Orphanet

familial thoracic aortic aneurysm and aortic dissectionDEFINITIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0019625

Submitter: ClinGen

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*MYH11* was first reported in relation to autosomal dominant congenital heart disease in 2017 (Pal et al., PMID: 28512736). At least four unique variants (missense, nonsense, splice-site, deletion) were reported in four individuals with CHD (PMID: 28512736, 32859249, 33084842), but only the splice-site variant was included in this curation. The rest were not scored due to presence of variants in other CHD-related genes or high frequencies on gnomAD v4. Of note, there are 4 CNVs encompassing *MYH11* and several other genes reported in individuals with CHD (PMIDs: 22318994, 23979609). In summary, there is limited evidence supporting the relationship between *MYH11* and autosomal dominant congenital heart disease. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date October 15th, 2024 (SOP Version 11).

visceral myopathy 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859157

Submitter: Ambry Genetics

visceral myopathy 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0859157

Submitter: Labcorp Genetics (formerly Invitae)

familial thoracic aortic aneurysm and aortic dissectionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: Orphanet

megacystis-microcolon-intestinal hypoperistalsis syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0025708

Submitter: G2P

aortic aneurysm, familial thoracic 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007568

Submitter: Ambry Genetics

aortic aneurysm, familial thoracic 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007568

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2AD/AR

Manifestation: Cardiovascular; Gastrointestinal; Genitourinary; Renal

Intervention: Cardiovascular; Gastrointestinal; Renal

Rationale: In Aortic aneurysm, familial thoracic 4, surveillance for aortic aneurysms and related anomalies (as well as PDA) can allow early detection and treatment, potentially decreasing morbidity and mortality; In Visceral myopathy 2, individuals have been described with a variety of gastrointestinal sequelae, some of which may benefit from medical and/or surgical interventions; Individuals with Megacystis-microcolon-intestinal hypoperistalsis syndrome may have anomalies such as intestinal and genitorenal anomalies, and awareness may allow prompt surgical and medical management

Refs: 11249915; 14722581; 16444274; 17666408; 22415348; 22968129; 25407000; 29575632; 31389005; 31427716; 31944481

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYH11 variants in ClinVar

37 Conditions Cataloged

Familial thoracic aortic aneurysm and aortic dissectionTotal: 2811

Aortic aneurysm, familial thoracic 4Total: 2402

not providedTotal: 926

not specifiedTotal: 399

Megacystis-microcolon-intestinal hypoperistalsis syndrome 2Total: 159

Visceral myopathy 2Total: 144

MYH11-related disorderTotal: 93

Lissencephaly 4Total: 54

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002474.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			25 clinvar	1051 clinvar	19 clinvar	1095
missense		7 clinvar	1859 clinvar	89 clinvar	10 clinvar	1965
nonsense	15 clinvar	14 clinvar	26 clinvar			55
start loss		1 clinvar				1
frameshift	18 clinvar	6 clinvar	24 clinvar			48
splice donor/acceptor (+/-2bp)	4 clinvar	28 clinvar	19 clinvar			51
Total	37	56	1953	1140	29	3215

Highest pathogenic variant AF is 0.000034716195

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002474.3	RefSeq	NP_002465.1	40	MANE Select
ENST00000300036.6	Ensembl	ENSP00000300036.5	40	MANE Select
NM_001040113.2	RefSeq	NP_001035202.1	41	MANE Plus Clinical
NM_001040114.2	RefSeq	NP_001035203.1	41	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
myh11a	Danio rerio	Structure: intestinal epithelial cell Quality: mislocalised abnormal

Gene / Model

Organism

Observed Phenotype

myh11a

Danio rerio

Structure: intestinal epithelial cell

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
Vascular smooth muscle contraction - Homo sapiens (human)
Developmental Biology
Smooth Muscle Contraction
Signal Transduction

Biological Process

muscle contraction
smooth muscle contraction
skeletal muscle myosin thick filament assembly
elastic fiber assembly
cardiac muscle fiber development

Molecular Function

motor activity
protein binding
calmodulin binding
ATP binding
structural constituent of muscle

Cellular Component

cytosol
muscle myosin complex
myosin filament
melanosome
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396324
Coding exons: 41
Length: 153862
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.44	985	1.12e+3	0.879	0.0000776	13102
Missense (PolyPhen)		343	494.75	0.69328		5974
Synonymous	-2.89	559	479	1.17	0.0000359	3639
Loss of Function	7.63	24	111	0.217	0.00000625	1275

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.00056	0.00056	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Muscle contraction.;
Disease: DISEASE: Note=A chromosomal aberration involving MYH11 is found in acute myeloid leukemia of M4EO subtype. Pericentric inversion inv(16)(p13;q22). The inversion produces a fusion protein consisting of the 165 N-terminal residues of CBF-beta (PEPB2) and the tail region of MYH11.; DISEASE: Aortic aneurysm, familial thoracic 4 (AAT4) [MIM:132900]: A disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance. {ECO:0000269|PubMed:16444274}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.400

Intolerance Scores

LoFtool: 0.00613
RVIS EVS: -3.1
RVIS percentile EVS: 0.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.694

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium