MYOM1
protein-codingmyomesin 1, the group of I-set domain containing|Myosin binding proteins
Gene summary
The giant protein titin, together with its associated proteins, interconnects the major structure of sarcomeres, the M bands and Z discs. The C-terminal end of the titin string extends into the M line, where it binds tightly to M-band constituents of apparent molecular masses of 190 kD (myomesin 1) and 165 kD (myomesin 2). This protein, myomesin 1, like myomesin 2, titin, and other myofibrillar proteins contains structural modules with strong homology to either fibronectin type III (motif I) or immunoglobulin C2 (motif II) domains. Myomesin 1 and myomesin 2 each have a unique N-terminal region followed by 12 modules of motif I or motif II, in the arrangement II-II-I-I-I-I-I-II-II-II-II-II. The two proteins share 50% sequence identity in this repeat-containing region. The head structure formed by these 2 proteins on one end of the titin string extends into the center of the M band. The integrating structure of the sarcomere arises from muscle-specific members of the superfamily of immunoglobulin-like proteins. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~153.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005045
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0005453
Submitter: LiferaOmics
Genetic evidence – Published (AR scope) No scorable published cases of biallelic (autosomal recessive) MYOM1 variants causing cardiovascular disease were identified. Published genetic evidence total = 0/12 Published (AD context; not scored for AR) ClinGen Gene–Disease Validity: MYOM1 – Hypertrophic cardiomyopathy (AD) has been curated by the Hereditary Cardiovascular Disease GCEP and classified as Disputed. The available evidence for monoallelic MYOM1 variants causing autosomal dominant HCM was considered insufficient to support a validated gene–disease relationship. PMID: 21256114 AD-context evidence total (not scored for AR) = 0 Genetic evidence – Our case Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous nonsense NM_003803.3:c.3101G>A, p.Trp1034Ter; AR predicted null default = 1.5; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0 (prior neonatal deaths not genotyped); Case-control = 0; Family 1 total = 1.0 Total genetic evidence (published AR + our case) 1.0/12 Experimental evidence – Published PMID: 33452765 – Demonstrates that MYOM1 is essential for sarcomere organization and cardiomyocyte structural integrity. MYOM1 knockout human stem-cell–derived cardiomyocytes showed impaired sarcomere assembly and contractile dysfunction, supporting a role for MYOM1 in cardiac muscle structure and function. Although these experiments do not establish a specific autosomal recessive human disorder, they provide biological plausibility that loss of MYOM1 affects cardiac tissue. Gene function / biological plausibility = 0.5 Experimental evidence total = 0.5/6 Overall score Genetic evidence = 1.0 Experimental evidence = 0.5 Overall score = 1.5
Inheritance Pattern: AD
Disease ID:MONDO:0024573
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0005045
Submitter: ClinGen
*MYOM1* was first reported in relation to hypertrophic cardiomyopathy (HCM) in humans in 2011 (Siegert et al, 2011, PMID 21256114). *MYOM1* has been associated with hypertrophic cardiomyopathy (HCM) in 11 probands across 4 publications (Siegert et al, 2011, PMID 21256114; Cecconi M, et al., 2016, PMID: 27600940; Bottillo I, et al., 2016, PMID: 26656175; Guo X, et al., 2017, PMID: 28323875). A single missense variant, p.Val1490Ile, segregated in 2 affected family members with HCM and destabilized dimerization of the MYOM1 protein; however, variants in all 8 sarcomeric genes were not ruled out (Siegert et al, 2011, PMID 21256114). Nine additional missense variants, one intronic variant, one splice-site variant, and a synonymous variant are included in this curation. All but one received reduced scores either due to the presence of variants in other HCM genes, inconsistent phenotypes, or high allele frequencies in gnomAD (Cecconi M, et al., 2016, PMID: 27600940; Bottillo I, et al., 2016, PMID: 26656175; Guo X, et al., 2017, PMID: 28323875). The mechanism for disease is unknown.This gene-disease relationship is supported by an expression study (Schoenauer et al, 2011, PMID 21069531). This gene-disease pair was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on July 20th, 2017. It was reevaluated by the Hereditary Cardiovascular Disease Gene Curation Expert Panel on February 23rd, 2023. As a result of this reevaluation, the classification was changed from limited to disputed.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MYOM1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003803.4. 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 | 11 | 475 | 2 | 488 | ||
| missense | 1 | 1073 | 66 | 8 | 1148 | |
| nonsense | 1 | 32 | 33 | |||
| start loss | 0 | |||||
| frameshift | 43 | 1 | 44 | |||
| splice donor/acceptor (+/-2bp) | 22 | 3 | 25 | |||
| Total | 0 | 2 | 1181 | 545 | 10 | 1738 |
Highest pathogenic variant AF is 0.000031618063
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003794.3 | 37 | MANE Select | |
| Ensembl | ENSP00000348821.4 | 37 | MANE Select | |
| RefSeq | NP_062830.1 | 36 | Standard | |
| Ensembl | ENSP00000261606.7 | 36 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Striated Muscle Contraction
Biological Process
- extraocular skeletal muscle development
- muscle contraction
- positive regulation of gene expression
- protein kinase A signaling
- skeletal muscle thin filament assembly
Molecular Function
- protein binding
- structural constituent of muscle
- kinase binding
- identical protein binding
- protein homodimerization activity
Cellular Component
- striated muscle myosin thick filament
- striated muscle thin filament
- sarcomere
- Z disc
- M band
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000356443
- Coding exons
- 37
- Length
- 153302
- Individuals with no LoFs
- 124445
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 251
- Defined
- 124696
- p
- 0.00101
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.618 | 920 | 974 | 0.944 | 0.0000579 | 10960 |
| Missense (PolyPhen) | 315 | 363.6 | 0.86634 | 4053 | ||
| Synonymous | -0.0177 | 377 | 377 | 1.00 | 0.0000244 | 3220 |
| Loss of Function | 1.93 | 73 | 93.1 | 0.784 | 0.00000492 | 1114 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0013 | 0.0011 | notable |
| Latino/Admixed American | 0.0015 | 0.0013 | notable |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.0023 | 0.0023 | notable |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00090 | 0.00088 | rare |
| South Asian | 0.0013 | 0.0012 | notable |
| Other | 0.00084 | 0.00083 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Major component of the vertebrate myofibrillar M band. Binds myosin, titin, and light meromyosin. This binding is dose dependent.;
Recessive Scores
- pRec
- 0.112
Intolerance Scores
- RVIS EVS
- 0.56
- RVIS percentile EVS
- 81.68
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.115
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |