rs74315329 — MYOC Gln368Ter (Q368X)

Pathogenic nonsense variant in myocilin causing autosomal dominant juvenile and adult-onset open-angle glaucoma through trabecular meshwork dysfunction and elevated intraocular pressure

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MYOC Gln368Ter — The Most Common Genetic Cause of Open-Angle Glaucoma

Glaucoma is the leading cause of irreversible blindness worldwide, affecting over 80 million people. Most cases are "open-angle" — the drainage angle of the eye looks normal under examination, yet fluid builds up and silently crushes the optic nerve over years. For a small but well-defined group of patients, the culprit is a single-letter change in the MYOC gene11 MYOC gene
MYOC (myocilin) encodes a glycoprotein secreted into the aqueous humor of the eye. Originally discovered as the trabecular meshwork-induced glucocorticoid response protein (TIGR), MYOC is highly expressed in the trabecular meshwork — the sponge-like tissue responsible for draining aqueous humor from the eye and regulating intraocular pressure. The Gln368Ter variant — also written Q368X or p.Gln368Ter — introduces a premature stop codon that truncates the myocilin protein at position 368, making it the most frequently identified single-gene cause of open-angle glaucoma in populations of European descent.

This variant is classified Pathogenic by ClinVar22 Pathogenic by ClinVar
ClinVar variation VCV000007949; reviewed by the ClinGen Glaucoma Variant Curation Expert Panel in January 2026 and awarded four stars — the highest review tier, signifying consensus among an independent panel of glaucoma genetics experts and listed as OMIM allelic variant 601652.0003. Unlike many "risk variants" that confer modest statistical elevation in population studies, Q368X reliably causes disease in the families in which it segregates — though its penetrance is incomplete and age-dependent.

The Mechanism

Myocilin is secreted into the aqueous humor and extracellular matrix of the trabecular meshwork, where it participates in maintaining the tissue architecture that regulates aqueous drainage. The Gln368Ter substitution (c.1102C>T in coding sequence; G>A at the plus-strand chromosomal level) introduces a premature stop codon at position 368, truncating the olfactomedin domain — the C-terminal functional region of the protein.

The critical insight is that truncated myocilin is not simply absent — it is retained inside the cell33 truncated myocilin is not simply absent — it is retained inside the cell
Studies show that mutant myocilin including Q368X accumulates in the endoplasmic reticulum rather than being properly secreted. This ER retention triggers unfolded protein response (UPR) stress and, over time, trabecular meshwork cell death. Mutant myocilin also activates the IL-1/NF-κB inflammatory pathway in trabecular meshwork cells — stimulating release of IL-1α and IL-1β — while wild-type myocilin normally suppresses this inflammatory cascade. The consequence is progressive trabecular meshwork dysfunction, impaired aqueous outflow, and chronically elevated intraocular pressure (IOP) that damages the optic nerve.

Because MYOC is also expressed in vascular endothelial cells and smooth muscle, dysfunction in myocilin may affect shared vascular regulatory pathways. The trabecular meshwork itself is a specialized vascular endothelial structure, and the vascular mechanisms maintaining IOP homeostasis overlap with systemic endothelial biology — providing a rationale for tracking this variant in the cardiovascular context of its heart-inflammation category.

The Evidence

The evidence for Q368X as a cause of open-angle glaucoma is among the strongest in ophthalmic genetics.

Cheng et al., 201244 Cheng et al., 2012
Cheng JW et al. Myocilin polymorphisms and primary open-angle glaucoma: a systematic review and meta-analysis. PLoS One 7(11):e50inner, 2012 — 32 case-control studies meta-analysed 32 case-control studies and found Q368X associated with POAG at an odds ratio of 4.68 (95% CI 2.02–10.85), rising to 5.17 in Western populations (95% CI 2.16–12.40). The association is stronger for high-tension glaucoma (OR 4.26), consistent with the IOP-elevating mechanism.

At the population level, MYOC mutations account for 3–5% of adult-onset POAG and 10–33% of juvenile-onset open-angle glaucoma (JOAG)55 juvenile-onset open-angle glaucoma (JOAG)
JOAG is defined as POAG with onset before age 40. It typically presents with much higher IOP (often >30 mmHg) than adult-onset POAG and frequently requires surgical intervention. MYOC mutations are far more prevalent in JOAG than in late-onset POAG. Q368X is the single most prevalent MYOC disease-causing mutation in European- ancestry populations.

The ClinGen Glaucoma Variant Curation Expert Panel's January 2026 review awarded Q368X the highest ClinVar review tier (4 stars, Pathogenic), reflecting segregation data from multiple affected families, the damaging nature of the stop-gain alteration, and functional evidence from trabecular meshwork cell studies.

Itakura et al., 201566 Itakura et al., 2015
Itakura T, Peters DM, Fini ME. Glaucomatous MYOC mutations activate the IL-1/NF-kappaB inflammatory stress response and the glaucoma marker SELE in trabecular meshwork cells. Mol Vis 21:1071–84, 2015 demonstrated that Q368X and other glaucoma-causing MYOC mutants robustly activate the IL-1/NF-κB axis — providing a mechanistic bridge between the genetic lesion and trabecular meshwork pathology.

Practical Actions

Identifying a Q368X carrier fundamentally changes ophthalmologic management: annual IOP measurement and optic nerve assessment is the cornerstone, since early detection of elevated IOP (before optic nerve damage) is the window where treatment is most effective. IOP-lowering therapy (topical prostaglandin analogues, beta-blockers, or surgical procedures such as trabeculectomy or minimally invasive glaucoma surgery) can halt progression if started before significant nerve fiber loss occurs. Carriers should inform first-degree relatives, each of whom has a 50% chance of inheriting this autosomal dominant variant.

Carriers should be counseled that penetrance is incomplete — not all Q368X carriers will develop clinical glaucoma, and age of onset varies widely — but the risk is high enough to justify lifelong ophthalmologic surveillance beginning in the second decade of life.

Interactions

MYOC Q368X interacts functionally with other glaucoma risk variants. Digenic inheritance has been described in MYOC: Q368X combined with variants in CYP1B1 (an enzyme involved in ocular metabolism) appears in some families with more severe early-onset glaucoma than expected from Q368X alone. Additionally, MYOC Gly399Val/Asp (rs28936694, the variant originally specified in this research brief) is a related MYOC missense variant at the adjacent codon 399 and has also been associated with digenic glaucoma. These interactions suggest that the MYOC olfactomedin domain is a hotspot for dominant glaucoma mutations, and compound carriers warrant closer surveillance.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-Carrier Normal

No MYOC Q368X variant — standard glaucoma risk from this gene

You carry two copies of the normal MYOC allele at this position and do not have the Q368X nonsense variant. Your risk of glaucoma from this specific mutation is not elevated. The Q368X allele is rare globally — present in roughly 1 in 400 Europeans and even rarer in other ancestries — so the large majority of people share this result. Other genetic and non-genetic factors (age, family history, IOP, corneal thickness) still contribute to glaucoma risk and are not captured here.

AG Q368X Carrier High Risk

Carries one copy of MYOC Q368X — pathogenic for open-angle glaucoma

MYOC Q368X (c.1102C>T; NM_000261.2:p.Gln368Ter) truncates the myocilin protein within its olfactomedin domain — a C-terminal region essential for proper folding and secretion. The truncated protein is not degraded efficiently and accumulates in the endoplasmic reticulum of trabecular meshwork cells. This retention activates the unfolded protein response (UPR) and the IL-1/ NF-κB inflammatory axis, stimulating release of pro-inflammatory cytokines (IL-1α, IL-1β) and the endothelial adhesion marker SELE. Over time, this leads to trabecular meshwork cell death, reduced aqueous outflow, and chronically elevated IOP.

Clinical features in Q368X carriers: - Intraocular pressure elevation (often substantial, >25 mmHg; juveniles may exceed 35–40 mmHg) - Progressive optic nerve cupping (cup-to-disc ratio enlargement) - Visual field loss beginning peripherally and advancing centrally - Juvenile onset (teens–30s) or adult onset (40s–70s), depending on penetrance in the individual - Open drainage angle on gonioscopy (despite drainage dysfunction) - Penetrance: estimated at 70–100% for elevated IOP across a lifetime; clinical glaucoma penetrance lower due to treatment and age effects

Effective IOP-lowering therapies exist: topical prostaglandin analogues (latanoprost, bimatoprost), beta-blockers (timolol), carbonic anhydrase inhibitors, and alpha-agonists. Laser trabeculoplasty and filtering surgery (trabeculectomy, MIGS) are available for refractory cases. The earlier treatment begins relative to optic nerve damage, the better the prognosis for maintaining vision.

AA Homozygous Q368X Homozygous

Carries two copies of MYOC Q368X — rare; severe early-onset glaucoma risk

You carry two copies of the MYOC Q368X variant, one on each chromosome 1. This is an exceptionally rare genotype — Q368X has a global frequency of approximately 0.12% (1 in 830 alleles), making homozygosity occur by chance in roughly 1 in 700,000 individuals. Homozygous cases have been documented in the literature and are associated with early-onset, often severe glaucoma requiring early surgical intervention. Both copies of myocilin produce truncated, non-functional protein, eliminating the protective anti-inflammatory function of normal myocilin entirely. Management is as urgent as for heterozygous carriers, with the additional certainty that all biological children will inherit at least one Q368X allele.