MYOC
protein-codingmyocilin
Gene summary
MYOC encodes the protein myocilin, which is believed to have a role in cytoskeletal function. MYOC is expressed in many occular tissues, including the trabecular meshwork, and was revealed to be the trabecular meshwork glucocorticoid-inducible response protein (TIGR). The trabecular meshwork is a specialized eye tissue essential in regulating intraocular pressure, and mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angle glaucoma. [provided by RefSeq, Jul 2008]
- GLC1A
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007664
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0020367
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0020366
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007664
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007664
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005338
Submitter: ClinGen
Variants in the *MYOC* gene were reported in human patients with open angle glaucoma as early as 1997 (Stone et al., PMID: 9005853). Patient phenotypes are most often reported as ocular hypertension and open angle glaucoma, and can also include increased cup to disc ratio in the optic disc, abnormal trabecular meshwork morphology, and/or optic neuropathy. At least 21 unique variants have been reported in human patients evaluated as part of this curation (19 missense, 1 in-frame indel, and 1 nonsense variant predicted to result in C-terminal truncation rather than nonsense-mediated decay). The variant types are consistent with the reported heterozygous gain of function mechanism. Variants in this gene have been reported in at least 26 probands in 15 publications (PMIDs: 9005853, 23517641, 27080696, 11774072, 9328473, 94902876, 32300215, 9639450, 10815160, 11004290, 9556305, 9521427, 9772276, 9832047, and 9863594). Variants in this gene segregated with disease in over 25 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has already been reached. The mechanism for disease has been experimentally shown to be heterozygous gain of function, with the mutant MYOC protein accumulating in the trabecular meshwork causing increased stress and early cellular apoptosis (PMID: 10545602). A fly model of the disease exhibits fluid discharge from overexpressed mutant or wildtype MYOC, which mirrors the human phenotype of increased intraocular pressure, and similarly causes rapid deterioration in visual function (PMID: 19148291). At the cellular level, the flies also exhibit the features of ER stress, unfolded protein response, and apoptosis thought to underlie the human disease state (PMID: 19148291). A mouse model expressing a human *MYOC* transgene exhibits accumulation of the mutant protein and increased stress in the trabecular meshwork, increased intraocular pressure, progressive retinal ganglion cell death, and optic nerve degeneration (PMID: 21821918). There is more evidence available in the literature, but the maximum score for experimental evidence has already been reached. In summary, *MYOC* is definitively associated with autosomal dominant open-angle glaucoma. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on February 17th, 2022 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0007664
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0020367
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
Intervention: Ophthalmologic; Pharmacogenomic
Rationale: Early diagnosis and treatment may be effective to decrease morbidity and mortality related to vision loss; Agents that may contribute to glaucoma should be avoided
Comments: Digenic inheritance (with CYP1B1) has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MYOC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000261.2. 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 | 24 | 29 | 6 | 59 | ||
| missense | 13 | 33 | 144 | 22 | 3 | 215 |
| nonsense | 2 | 13 | 1 | 16 | ||
| start loss | 0 | |||||
| frameshift | 15 | 15 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 15 | 33 | 197 | 52 | 9 | 306 |
Highest pathogenic variant AF is 0.0011586308
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000252.1 | 3 | MANE Select | |
| Ensembl | ENSP00000037502.5 | 3 | MANE Select | |
| Ensembl | ENSP00000491206.1 | 3 | Standard | |
| Ensembl | ENSP00000547982.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- osteoblast differentiation
- negative regulation of cell-matrix adhesion
- positive regulation of phosphatidylinositol 3-kinase signaling
- skeletal muscle hypertrophy
- myelination in peripheral nervous system
Molecular Function
- fibronectin binding
- frizzled binding
- protein binding
- receptor tyrosine kinase binding
- myosin light chain binding
Cellular Component
- extracellular space
- mitochondrial outer membrane
- mitochondrial inner membrane
- mitochondrial intermembrane space
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000037502
- Coding exons
- 3
- Length
- 17267
- Individuals with no LoFs
- 125151
- Homozygous LoFs
- 3
- Heterozygous LoFs
- 594
- Defined
- 125748
- p
- 0.00238
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.520 | 253 | 277 | 0.912 | 0.0000158 | 3280 |
| Missense (PolyPhen) | 64 | 91.106 | 0.70248 | 1113 | ||
| Synonymous | -0.0927 | 115 | 114 | 1.01 | 0.00000652 | 1013 |
| Loss of Function | 0.638 | 19 | 22.2 | 0.854 | 0.00000158 | 224 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0021 | 0.0021 | notable |
| Latino/Admixed American | 0.00061 | 0.00061 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0097 | 0.0097 | notable |
| Finnish | 0.0042 | 0.0042 | notable |
| European (Non-Finnish) | 0.0020 | 0.0020 | notable |
| South Asian | 0.0013 | 0.0013 | notable |
| Other | 0.00082 | 0.00081 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration. Promotes substrate adhesion, spreading and formation of focal contacts. Negatively regulates cell-matrix adhesion and stress fiber assembly through Rho protein signal transduction. Modulates the organization of actin cytoskeleton by stimulating the formation of stress fibers through interactions with components of Wnt signaling pathways. Promotes cell migration through activation of PTK2 and the downstream phosphatidylinositol 3-kinase signaling. Plays a role in bone formation and promotes osteoblast differentiation in a dose-dependent manner through mitogen-activated protein kinase signaling. Mediates myelination in the peripheral nervous system through ERBB2/ERBB3 signaling. Plays a role as a regulator of muscle hypertrophy through the components of dystrophin-associated protein complex. Involved in positive regulation of mitochondrial depolarization. Plays a role in neurite outgrowth. May participate in the obstruction of fluid outflow in the trabecular meshwork. {ECO:0000250|UniProtKB:O70624, ECO:0000269|PubMed:17516541, ECO:0000269|PubMed:17984096, ECO:0000269|PubMed:18855004, ECO:0000269|PubMed:19188438, ECO:0000269|PubMed:19959812, ECO:0000269|PubMed:21656515, ECO:0000269|PubMed:23629661, ECO:0000269|PubMed:23897819}.;
- Disease
- DISEASE: Glaucoma 1, open angle, A (GLC1A) [MIM:137750]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. {ECO:0000269|PubMed:10196380, ECO:0000269|PubMed:10330365, ECO:0000269|PubMed:10340788, ECO:0000269|PubMed:10644174, ECO:0000269|PubMed:10798654, ECO:0000269|PubMed:10819638, ECO:0000269|PubMed:10873982, ECO:0000269|PubMed:10916185, ECO:0000269|PubMed:10980537, ECO:0000269|PubMed:11004290, ECO:0000269|PubMed:11774072, ECO:0000269|PubMed:12189160, ECO:0000269|PubMed:12356829, ECO:0000269|PubMed:12362081, ECO:0000269|PubMed:12442283, ECO:0000269|PubMed:12860809, ECO:0000269|PubMed:12872267, ECO:0000269|PubMed:15025728, ECO:0000269|PubMed:15255110, ECO:0000269|PubMed:15534471, ECO:0000269|PubMed:15795224, ECO:0000269|PubMed:16401791, ECO:0000269|PubMed:17210859, ECO:0000269|PubMed:17499207, ECO:0000269|PubMed:25524706, ECO:0000269|PubMed:9005853, ECO:0000269|PubMed:9328473, ECO:0000269|PubMed:9345106, ECO:0000269|PubMed:9361308, ECO:0000269|PubMed:9490287, ECO:0000269|PubMed:9510647, ECO:0000269|PubMed:9521427, ECO:0000269|PubMed:9535666, ECO:0000269|PubMed:9697688, ECO:0000269|PubMed:9792882, ECO:0000269|PubMed:9863594}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glaucoma 3, primary congenital, A (GLC3A) [MIM:231300]: An autosomal recessive form of primary congenital glaucoma (PCG). PCG is characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor. {ECO:0000269|PubMed:15733270}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. MYOC mutations may contribute to GLC3A via digenic inheritance with CYP1B1 and/or another locus associated with the disease (PubMed:15733270). {ECO:0000269|PubMed:15733270}.;
Recessive Scores
- pRec
- 0.410
Intolerance Scores
- LoFtool
- 0.209
- RVIS EVS
- -0.13
- RVIS percentile EVS
- 43.91
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.594
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |