MYH2

protein-coding

myosin heavy chain 2, the group of Myosin heavy chains, class II

Gene summary

Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

Previous symbols:

IBM3

MANE transcript

NM_017534.6

Inheritance

AR, SD, AD

ClinVar variants

P:133U:903B:366

Top phenotype

Congenital myopathy 6 with ophthalmoplegia

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr17:10,521,148-10,549,700

External References & Databases

Ensembl (ENSG00000125414)

Transcript & Mutation Effects

hg38 • Region Span ~28.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myopathy, proximal, and ophthalmoplegiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011577

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

childhood-onset autosomal recessive myopathy with external ophthalmoplegiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018206

Submitter: Orphanet

myopathy, proximal, and ophthalmoplegiaSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0011577

Submitter: Ambry Genetics

myopathy, proximal, and ophthalmoplegiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011577

Submitter: ClinGen

*MYH2* was first reported in relation to autosomal recessive proximal myopathy and ophthalmoplegia in 2000 (Tajsharghi et al., PMID: 20418530). Evidence supporting this gene-disease relationship includes case-level data from 8 probands in 3 publications (PMIDs: 20418530, 23388406, 24193343), with ten unique variants (including missense, in-frame deletions, frameshifts, and splice sites), having a loss of function mechanism. This gene-disease association is also supported by experimental evidence, including expression evidence (PMID: 7545970) in type IIa muscle fibers and a C. elegans model (PMID: 16130113). In summary, *MYH2* is definitively associated with autosomal recessive proximal myopathy and ophthalmoplegia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, *MYH2* has also been reported in relation to autosomal dominant proximal myopathy and ophthalmoplegia. Due to the proposed difference in mechanism, dominant negative, those cases were considered in a separate curation.

myopathy, proximal, and ophthalmoplegiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011577

Submitter: PanelApp Australia

myopathy, proximal, and ophthalmoplegiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011577

Submitter: Labcorp Genetics (formerly Invitae)

myopathy, proximal, and ophthalmoplegiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011577

Submitter: Labcorp Genetics (formerly Invitae)

myopathy, proximal, and ophthalmoplegiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011577

Submitter: PanelApp Australia

hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019195

Submitter: Orphanet

hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019195

Submitter: Illumina

myopathy, proximal, and ophthalmoplegiaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011577

Submitter: ClinGen

*MYH2* was first reported in relation to autosomal dominant proximal myopathy and ophthalmoplegia in 2000 (Martinsson et al., PMID: 11114175). Evidence supporting this gene-disease relationship includes case-level data from 7 probands in 6 publications (PMIDs: 11114175, 23489661, 25529940, 36380287, 36774715,41252304), with five unique variants (4 missense and 1 splice site) predominantly found in the filament assembly region except for Glu706Lys in the SH1 helix domain. A dominant negative mechanism has been suggested however has not been established. This gene-disease association is also supported by experimental evidence, including expression evidence (PMID: 7545970) in type IIa muscle fibers, functional alteration in patient cells (PMID: 17005402), and a C. elegans model (PMID: 16130113). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Congenital Myopathies and Myasthenic Syndromes GCEP on June 10, 2024. It was re-evaluated on June 10, 2026. As a result of this reevaluation, the classification remained Moderate with the addition of 2 new cases (PMID: 41252304). Of note, *MYH2* has also been reported in relation to autosomal recessive proximal myopathy and ophthalmoplegia. Due to the proposed difference in mechanism, loss of function, those cases were considered in a separate curation.

Clinical Genomic Database (CGD)

Congenital myopathy 6 with ophthalmoplegiaAD/AR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 11114175; 24193343

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYH2 variants in ClinVar

14 Conditions Cataloged

Myopathy, proximal, and ophthalmoplegiaTotal: 1449

not providedTotal: 269

Inborn genetic diseasesTotal: 254

MYH2-related disorderTotal: 49

not specifiedTotal: 48

MyopathyTotal: 2

Childhood-onset autosomal recessive myopathy with external ophthalmoplegiaTotal: 1

Hereditary spherocytosis type 2Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017534.6. 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			21 clinvar	333 clinvar	5 clinvar	359
missense	3 clinvar	7 clinvar	873 clinvar	26 clinvar	2 clinvar	911
nonsense	24 clinvar	13 clinvar	2 clinvar			39
start loss			3 clinvar			3
frameshift	37 clinvar	15 clinvar	4 clinvar			56
splice donor/acceptor (+/-2bp)	4 clinvar	30 clinvar				34
Total	68	65	903	359	7	1402

Highest pathogenic variant AF is 0.000065672575

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017534.6	RefSeq	NP_060004.3	38	MANE Select
ENST00000245503.10	Ensembl	ENSP00000245503.5	38	MANE Select
NM_001100112.2	RefSeq	NP_001093582.1	38	Standard
ENST00000397183.6	Ensembl	ENSP00000380367.2	38	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
amb2 Integrin signaling
Alpha4 beta1 integrin signaling events

Biological Process

muscle contraction
muscle filament sliding
Fc-gamma receptor signaling pathway involved in phagocytosis

Molecular Function

microfilament motor activity
protein binding
calmodulin binding
ATP binding
actin filament binding

Cellular Component

cytosol
muscle myosin complex
myofibril
sarcomere
myosin filament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000245503
Coding exons: 38
Length: 28810
Individuals with no LoFs: 125566
Homozygous LoFs: 0
Heterozygous LoFs: 182
Defined: 125748
p: 0.000724

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.97	826	1.00e+3	0.825	0.0000599	12909
Missense (PolyPhen)		254	325.4	0.78059		4458
Synonymous	-0.693	404	387	1.04	0.0000228	3539
Loss of Function	4.15	53	97.1	0.546	0.00000527	1244

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00098	0.00093	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00071	0.00071	rare
Finnish	0.0017	0.0017	notable
European (Non-Finnish)	0.00059	0.00057	rare
South Asian	0.00088	0.00088	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Muscle contraction. Required for cytoskeleton organization (By similarity). {ECO:0000250}.;
Disease: DISEASE: Myopathy, proximal, and ophthalmoplegia (MYPOP) [MIM:605637]: A muscular disorder characterized by mild-to- moderate muscle weakness, ophthalmoplegia, and contractures at birth in some patients. Muscle biopsies from patients show predominance of type 1 fibers and small or absent type 2A fibers. The disease is non-progressive or it progresses very slowly. Inheritance is autosomal dominant or recessive. {ECO:0000269|PubMed:11114175}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.231

Intolerance Scores

LoFtool: 0.0360
RVIS EVS: -2.09
RVIS percentile EVS: 1.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.611

Gene Damage Prediction

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