MYOC

Chr 1AD

myocilin

Also known as: GLC1A, GPOA, JOAG, JOAG1, TIGR

NCBI Gene: 4653 ENSG00000034971 UniProt: Q99972 OMIM: 601652

Myocilin is a secreted glycoprotein that regulates cell adhesion, cytoskeleton organization, and fluid outflow in the trabecular meshwork of the eye. Mutations cause autosomal dominant juvenile-onset primary open-angle glaucoma (Glaucoma 1A). The gene is not highly constrained against loss-of-function variants, consistent with its association with a specific tissue-related phenotype rather than systemic developmental abnormalities.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 1.251 OMIM phenotype

Clinical Summary— MYOC

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Gene-Disease Validity (ClinGen)

open-angle glaucoma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

50 unique Pathogenic / Likely Pathogenic· 204 VUS of 331 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.25LOEUF

pLI 0.000

Z-score 0.64

OE 0.85 (0.59–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.52Z-score

OE missense 0.91 (0.82–1.01)

253 obs / 277.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.85 (0.59–1.25)

0≤0.351.4

Missense OE?0.91 (0.82–1.01)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 19 / 22.2Missense obs/exp: 253 / 277.4Syn Z: -0.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMYOC-related juvenile open angle glaucomaOTHERAD

definitiveMYOC-related glaucoma, primary open angleLOFAD

This gene — mechanism propensity

0.6455th %ile

GOF

0.4973th %ile

LOF

0.3939th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOF1 literature citation · 96% of P/LP are missense

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNCell culture and mouse studies suggest that MYOC mutations cause glaucoma through a dominant-negative effect on myocilin protein secretion.1

GOFShepard et al. (2007) concluded that these data support a unique gain-of-function role for MYOC in glaucoma, contingent upon the interaction of mutant myocilin with PTSR1, and they noted that this was the first demonstration of a disease resulting from mutation-induced exposure of a cryptic signalin2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

331 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic35

VUS204

Likely Benign51

Benign26

Pathogenic

Likely Pathogenic

204

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	13	0	0	15
Likely Pathogenic	0	35	0	0	35
VUS	30	143	7	24	204
Likely Benign	1	22	4	24	51
Benign	0	4	15	7	26
Total	33	217	26	55	331

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

26 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap MYOC — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →