Leber congenital amaurosis: genes and variants

Genes linked to Leber congenital amaurosis

• CRB1: Protein crumbs homolog 1

  It helps maintain apical polarity and structural organization of photoreceptors and Muller glia in the retina. Biallelic pathogenic variants cause inherited retinal dystrophies including Leber congenital amaurosis and retinitis pigmentosa.

  141 disease-causing and 501 uncertain variants in CRB1 are linked to Leber congenital amaurosis.

• RPE65: Retinoid isomerohydrolase

  It regenerates 11-cis-retinoid chromophore in the retinal pigment epithelium, allowing visual pigments to recover after light exposure. Biallelic loss-of-function variants cause severe inherited retinal dystrophy, and RPE65-associated disease is treatable with approved gene-replacement therapy.

  29 disease-causing and 195 uncertain variants in RPE65 are linked to Leber congenital amaurosis.

• CRX: Cone-rod homeobox protein

  It activates photoreceptor-specific gene programs required for development and maintenance of rods and cones. Pathogenic variants can cause cone-rod dystrophy, Leber congenital amaurosis, or dominant retinitis pigmentosa depending on the molecular mechanism.

  11 disease-causing and 125 uncertain variants in CRX are linked to Leber congenital amaurosis.

• CEP290: Centrosomal protein of 290 kDa

  It organizes the transition zone of primary and sensory cilia and is essential for ciliary protein trafficking, especially in photoreceptors. Biallelic pathogenic variants cause a broad ciliopathy spectrum including Leber congenital amaurosis, Joubert syndrome, and nephronophthisis-related disease.

  1 disease-causing and 126 uncertain variants in CEP290 are linked to Leber congenital amaurosis.

• ALMS1: Centrosome-associated protein ALMS1

  It contributes to primary-cilium function, intracellular trafficking, and metabolic homeostasis in multiple tissues. Biallelic pathogenic variants cause Alstrom syndrome, which typically combines retinal degeneration, hearing loss, obesity, insulin resistance, and cardiomyopathy.

  1 disease-causing and 0 uncertain variants in ALMS1 are linked to Leber congenital amaurosis.

• ABCA4: Retinal-specific phospholipid-transporting ATPase ABCA4

  It flips retinal-derived lipid adducts across photoreceptor disc membranes so they can be cleared during the visual cycle. Biallelic loss-of-function variants cause Stargardt disease and can also produce cone-rod dystrophy or retinitis pigmentosa.

  0 disease-causing and 0 uncertain variants in ABCA4 are linked to Leber congenital amaurosis.

Weakly linked (only a few uncertain records): PDE6B and WDR19.

Where Leber congenital amaurosis variants cluster

• CRX Homeobox (positions 39–98): 11 of 11 disease-causing changes, 5.0× more than its size predicts.
• CRB1 Laminin G-like 2 (positions 714–885): 28 of 141 disease-causing changes, 1.6× more than its size predicts.
• CRB1 EGF-like 19 (positions 1297–1333): 8 of 141 disease-causing changes, 2.2× more than its size predicts.
• CRB1 EGF-like 11 (positions 441–481): 8 of 141 disease-causing changes, 1.9× more than its size predicts.
• CRB1 EGF-like 12 (positions 672–708): 7 of 141 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Leber congenital amaurosis

Showing 60 of 183.

Uncertain variants in Leber congenital amaurosis that look disease-causing

Which prediction tools work for Leber congenital amaurosis

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• AlphaMissense: 96 out of 100
• REVEL: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 90 out of 100
• SIFT: 87 out of 100
• MutPred2: 80 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 75 out of 100

Same protein, different disease

• RPE65-related recessive retinopathy is also caused by RPE65 variants; they fall partly in the same places as the Leber congenital amaurosis variants (83 disease-causing).
• Alstrom syndrome is also caused by ALMS1 variants; they fall mostly in different places as the Leber congenital amaurosis variants (4 disease-causing).
• CEP290-related ciliopathy is also caused by CEP290 variants; they fall mostly in different places as the Leber congenital amaurosis variants (7 disease-causing).
• Joubert syndrome is also caused by CEP290 variants; they fall mostly in different places as the Leber congenital amaurosis variants (5 disease-causing).

Diseases related to Leber congenital amaurosis

• Retinitis pigmentosa, also linked to ABCA4, ALMS1, CEP290, CRB1 and 2 more
• Cone-rod dystrophy, also linked to ABCA4, CRB1 and CRX
• Autosomal recessive retinitis pigmentosa, also linked to ABCA4, CRB1 and RPE65
• Severe early-childhood-onset retinal dystrophy, also linked to ABCA4 and CRB1
• Bardet-Biedl syndrome, also linked to ALMS1 and CEP290
• Monogenic diabetes, also linked to ALMS1
• RPE65-related recessive retinopathy, also linked to RPE65
• ABCA4-related retinopathy, also linked to ABCA4
• Stargardt disease, also linked to ABCA4
• Age related macular degeneration 9, also linked to ABCA4
• Retinal disorder, also linked to ABCA4
• Pigmented paravenous retinochoroidal atrophy, also linked to CRB1

Frequently asked questions

Which genes are linked to Leber congenital amaurosis?

In CATVariant, Leber congenital amaurosis is linked to 6 analyzed proteins: CRB1 (Protein crumbs homolog 1), RPE65 (Retinoid isomerohydrolase), CRX (Cone-rod homeobox protein), CEP290 (Centrosomal protein of 290 kDa), ALMS1 (Centrosome-associated protein ALMS1) and ABCA4 (Retinal-specific phospholipid-transporting ATPase ABCA4).

How many genetic variants are linked to Leber congenital amaurosis?

1,279 variants: 183 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 947 are of uncertain significance or have conflicting reports.

Which uncertain variants in Leber congenital amaurosis look disease-causing?

15 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example RPE65 F70V, CRB1 G1288D, CRB1 C394Y, CRB1 G899V and CRB1 C438Y. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Leber congenital amaurosis?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 28 disease-causing and 29 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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