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LCA5
lebercilin LCA5
LCA5 is located on the long (q) arm of chromosome 6, at band 6q14.1. Arm ratio per GRCh38 - banding schematic.
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Overview
LCA5 is located on chromosome 6 and encodes a 697-amino acid protein called lebercilin. This protein plays a structural role within the connecting cilium of photoreceptor cells, the specialised light-detecting neurons in the retina. The connecting cilium serves as a transport corridor, shuttling proteins and other molecules between the inner and outer segments of photoreceptors. When lebercilin function is compromised, this transport machinery fails, causing photoreceptor degeneration and progressive vision loss. The gene was identified through studies of families with early-onset retinal dystrophy, and pathogenic variants are now recognised as a cause of severe inherited eye disease.
What the gene does
Lebercilin functions primarily within the ciliary compartment of photoreceptor cells. Cilia are microtubule-based structures that project from the cell surface, and in photoreceptors they form a narrow bridge - the connecting cilium - between the inner segment (which houses the cell's metabolic machinery) and the outer segment (which contains the light-sensitive photopigments). Lebercilin is thought to contribute to the structural integrity of this ciliary bridge and to facilitate intraflagellar transport, the process by which cargo proteins move along the ciliary axoneme. Research suggests that lebercilin interacts with other ciliary proteins to maintain the organisation of the connecting cilium. Without functional lebercilin, photoreceptors cannot sustain the continuous renewal of their outer segments, leading to cellular dysfunction and eventual cell death. The protein's role appears to be particularly critical during retinal development and in the ongoing maintenance of mature photoreceptor cells.
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Chromosome location
LCA5 is located on the long arm of chromosome 6 at position 6q14.1. This region of chromosome 6 contains several genes involved in sensory and developmental processes. The genomic structure of LCA5 and the number of exons it comprises have been characterised through sequencing studies of affected families, though detailed transcript annotations continue to be refined as additional variants are identified in clinical practice.
Protein structure
Lebercilin is a 697-amino acid protein with a domain architecture characterised by extensive disordered regions and two coiled-coil motifs. The N-terminal portion includes a disordered region spanning amino acids 1 to 90, which may provide flexibility for protein-protein interactions. Two coiled-coil domains are present: the first extends from amino acids 103 to 297, and the second from amino acids 389 to 485. Coiled coils are helical structures that typically mediate protein dimerisation or oligomerisation, suggesting that lebercilin may form multi-protein complexes within the cilium. Additional disordered regions are found at amino acids 412 to 432, 522 to 548, and 606 to 697. These intrinsically disordered segments often serve as interaction hubs or regulatory sites, allowing the protein to adapt its conformation in response to binding partners or cellular signals.
Key variants
Pathogenic variants in LCA5 include nonsense mutations, frameshift deletions, and splice-site alterations that disrupt normal protein production. Most pathogenic changes lead to either a truncated protein or to nonsense-mediated decay of the mutant transcript, resulting in loss of functional lebercilin. Missense variants affecting the coiled-coil domains may also impair protein stability or interaction with ciliary partners. Carrier frequencies for LCA5 variants vary across populations, with certain variants observed recurrently in specific ethnic groups.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.110C>A | p.Ser37Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 5 |
c.1550_1551del | p.Arg517fs | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 5 |
c.1730dup | p.Leu577fs | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 5 |
c.1A>G | p.Met1Val | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 5 |
c.3G>A | p.Met1Ile | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis |
c.407del | p.Ser135_Leu136insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 5 |
c.42_45del | p.Lys15fs | Pathogenic | ★★☆☆ | Leber congenital amaurosis 5 |
c.609del | p.Leu203fs | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 5 |
c.721-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 5 |
c.753_754del | p.Asn251fs | Pathogenic/Likely pathogenic | ★★☆☆ | Leber congenital amaurosis 5 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in LCA5 are associated with inherited retinal dystrophies, typically presenting in infancy or early childhood. Affected individuals generally experience severe visual impairment, nystagmus (involuntary eye movements), and progressive degeneration of photoreceptor cells. The clinical presentation can range from congenital blindness to later-onset retinal degeneration, depending on the nature and location of the variants. Retinal imaging often reveals characteristic changes in the photoreceptor layer, and electroretinography demonstrates markedly reduced or absent retinal responses.
No disease links recorded for this gene in our reference set.
UK clinical status
LCA5 is included on the NHS Genomic Medicine Service Retinal Disorders panel with green classification (R32 version). Green status indicates that there is strong evidence supporting the gene's role in inherited retinal disease, and variants in LCA5 are reportable in diagnostic settings within the NHS. Individuals with suspected inherited retinal dystrophy may be offered testing that includes LCA5 as part of a multi-gene panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the LCA5 gene do?
LCA5 encodes lebercilin, a protein that maintains the structure and transport function of cilia in photoreceptor cells. These cilia are essential for the ongoing health and light-sensing ability of retinal cells.
How are LCA5 variants inherited?
LCA5-related retinal dystrophy typically follows an autosomal recessive pattern, meaning that an individual must inherit pathogenic variants from both parents to develop the condition. Carriers of a single variant generally do not experience vision problems.
Is genetic testing for LCA5 available on the NHS?
Yes, LCA5 is included on the NHS Retinal Disorders panel. Testing may be offered to individuals with clinical features of inherited retinal dystrophy, particularly when symptoms begin in infancy or early childhood.