rs28936700 — CYP1B1 Gly61Glu (G61E)

Pathogenic missense variant in the cytochrome P450 1B1 enzyme that abolishes most enzyme activity, causing primary congenital glaucoma and reduced estrogen hydroxylation capacity

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CYP1B1 G61E — The Glaucoma-Causing Enzyme Variant

The CYP1B1 enzyme plays two distinct biological roles: it is both a steroid-hormone metabolizer (converting estradiol to catechol estrogens) and a first-line activator of environmental procarcinogens including polycyclic aromatic hydrocarbons11 polycyclic aromatic hydrocarbons
PAHs: carcinogenic compounds found in tobacco smoke and grilled meat. This dual function makes CYP1B1 important across several health domains — but the p.Gly61Glu variant (rs28936700) is best known as the most common cause of primary congenital glaucoma (PCG) in Middle Eastern and North African populations, where it accounts for up to 63% of genetic glaucoma cases.

The Mechanism

Glycine at position 61 sits near the N-terminal membrane anchor of the CYP1B1 protein, within a structurally critical hinge region. Substituting glutamic acid at this position — a charged amino acid replacing a small neutral one — disrupts protein folding and significantly destabilizes the enzyme. Functional assays show the G61E variant retains only about 25% of wild-type CYP1B1 activity22 the G61E variant retains only about 25% of wild-type CYP1B1 activity
ClinVar VCV000007730 — functional studies demonstrating reduced 17β-estradiol hydroxylation and reduced benzo[a]pyrene metabolism, with markedly reduced protein expression in cell-based models.

CYP1B1 is expressed in the trabecular meshwork — the drainage tissue of the eye — and appears to metabolize an as-yet-unidentified signaling molecule essential for normal anterior eye development. When both copies of CYP1B1 are non-functional (homozygous or compound heterozygous), the trabecular meshwork fails to develop normally, leading to elevated intraocular pressure from birth and, without prompt surgical treatment, irreversible optic nerve damage.

The Evidence

Badeeb et al. (2014)33 Badeeb et al. (2014)
CYP1B1 mutations in patients with primary congenital glaucoma from Saudi Arabia. BMC Med Genet. screened 34 Saudi PCG patients and found that p.Gly61Glu was present in 63% of solved cases (17/27), predominantly homozygous, making it by far the most frequent pathogenic variant in this population. Severe phenotypes (corneal diameter >14mm, IOP >30 mmHg) were found in 50% of severely affected patients carrying this mutation.

Hilal et al. (2010)44 Hilal et al. (2010)
Screening of CYP1B1 and MYOC in Moroccan PCG families. Mol Vis. found G61E in 7.77% of Moroccan PCG probands (second most common variant after g.4339delG), suggesting a shared founder-effect haplotype across Middle East/North Africa.

Reis et al. (2016)55 Reis et al. (2016)
Analysis of CYP1B1 in pediatric and adult glaucoma. Mol Vis. confirmed that G61E is recurrent across multiple PCG phenotypes and anterior segment dysgenesis, and noted that heterozygous carriers of CYP1B1 loss-of-function variants may have elevated adult-onset primary open-angle glaucoma risk.

Alghamdi et al. (2020)66 Alghamdi et al. (2020)
Loss of microglia activities facilitates glaucoma progression. PLoS One. specifically studied p.Gly61Glu and found that cells carrying this mutation show 60% microglia hypoactivation by 72 hours, 71% pre-apoptotic microglia (vs 13% in controls), and differential expression of 27 cytokines — suggesting that progressive neuroinflammation and impaired optic nerve immune surveillance compound the structural trabecular meshwork defect.

Globally, the T allele frequency is approximately 0.02% (gnomAD). In Middle Eastern populations it reaches ~0.6%, consistent with a population founder effect. At the gnomAD Middle Eastern frequency, roughly 1 in 170 people carry one copy.

Practical Actions

For heterozygous carriers (CT genotype): there is no childhood eye disease, but emerging evidence suggests heterozygous CYP1B1 loss-of-function variants may modestly increase adult-onset open-angle glaucoma risk. Annual intraocular pressure checks with an ophthalmologist from age 40 are prudent, particularly given family history context.

For homozygous or compound heterozygous individuals (two pathogenic CYP1B1 alleles): primary congenital glaucoma typically manifests in infancy with tearing, light sensitivity, and corneal haze. This is a pediatric surgical emergency — timely goniotomy or trabeculotomy is the primary treatment. Neonatal ophthalmologic screening and early specialist referral are critical.

CYP1B1 also metabolizes estrogens; carriers have somewhat reduced 17β-estradiol hydroxylation capacity, though this is less clinically significant for single-copy carriers than the glaucoma risk.

Interactions

CYP1B1 interacts with CYP1A1 and COMT in the catechol estrogen pathway. rs1056836 (CYP1B1 Leu432Val) is a separate functional variant in the same enzyme that modulates estrogen and procarcinogen metabolism — it is common and codominant, unlike this rare pathogenic variant. In carriers of both rs28936700 (one copy) and rs1056836 risk alleles, the overall CYP1B1 enzyme output is further reduced, potentially affecting catechol estrogen balance. This interaction warrants a compound action if both variants are identified together. Separately, CYP1B1 interacts with SULT1E1 (rs1238574) in estrogen inactivation pathways.

Nutrient Interactions

estradiol impaired_conversion

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-Carrier Normal

No CYP1B1 G61E variant detected

You carry two copies of the common CYP1B1 sequence at this position. You do not carry the Gly61Glu pathogenic variant that causes primary congenital glaucoma in populations of Middle Eastern or North African ancestry. This is the typical result for people outside these populations — the T allele frequency is approximately 0.02% globally.

CT Carrier Carrier

Single-copy carrier — no childhood eye disease, modest adult glaucoma risk

CYP1B1 is expressed in the trabecular meshwork, the drainage tissue that regulates intraocular pressure. With one non-functional copy, enzyme activity is reduced but still sufficient for normal eye development. Studies such as Reis et al. (2016, PMID 27777502) found that heterozygous CYP1B1 variants — particularly loss-of-function alleles — may contribute to primary open-angle glaucoma in adulthood through sub-threshold trabecular dysfunction. This risk is substantially lower than for homozygous carriers and does not warrant urgent intervention, but regular intraocular pressure monitoring from middle age is a sensible precaution.

Your single functional CYP1B1 allele also means slightly reduced capacity to hydroxylate estradiol and metabolize some environmental procarcinogens, though these effects are modest compared to the common Leu432Val polymorphism (rs1056836) which operates in the same enzyme at a different site.

If you are of Middle Eastern or North African ancestry and planning a family, genetic counseling is worthwhile since your partner could also be a carrier, giving a 25% risk of an affected child (two non-functional copies) in each pregnancy.

TT Homozygous Homozygous

Two copies of the pathogenic G61E variant — primary congenital glaucoma risk

Primary congenital glaucoma caused by homozygous CYP1B1 G61E manifests with elevated intraocular pressure (typically >21 mmHg, often much higher), enlarged corneal diameter (buphthalmos), corneal edema, and characteristic optic nerve cupping — all detectable in the first months of life.

Functional data show that the Gly61Glu substitution reduces CYP1B1 enzyme activity to approximately 25% of wild-type, with significantly decreased protein expression (ClinVar VCV000007730). Alghamdi et al. (2020, PMID 33170892) showed that this mutation triggers microglia hypoactivation (60% decline by 72 hours) and neuroinflammation — implicating an immune surveillance deficit in progressive optic nerve damage beyond the primary trabecular meshwork defect.

Surgical treatment (goniotomy or trabeculotomy) is the primary intervention for PCG and has a high success rate when performed early. Medical management of IOP (topical beta-blockers, carbonic anhydrase inhibitors) can be used as a bridge to surgery. Adult survivors of PCG with this genotype require lifetime glaucoma monitoring because trabecular meshwork function remains impaired.

CYP1B1 homozygosity also nearly eliminates the enzyme's estrogen-hydroxylation and procarcinogen-metabolism functions, though the glaucoma phenotype dominates clinical management.