rs74315329 — MYOC Gln368Ter (Q368X)

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.