AGBL5 was first described in relation to retinitis pigmentosa in 2015 (Kastner et al., PMID: 26720455). Patients diagnosed with the specific disease entity, retinitis pigmentosa 75 (MONDO:0014871, OMIM:615900), most commonly exhibited rod-cone dystrophy, nyctalopia, reduced visual acuity, bone spicule pigmentation of the retina, cataracts, and/or constriction of peripheral visual fields. All of the probands were diagnosed during adulthood, although onset of ocular symptoms could occur during childhood. Many probands were also found to have hearing loss. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (biallelic loss of function in the AGBL5 gene product) and mode of inheritance (autosomal recessive) were found to be consistent among unrelated patients with this diagnosis. The phenotypic variability among the diverse cases appeared to represent a spectrum of disease rather than separate disease entities. Therefore, these cases have been lumped for the purposes of this gene curation into a single disease entity, referred to as AGBL5-related retinopathy.
This curation includes 16 variants (9 missense, 2 frameshift, 4 nonsense, and 1 non-canonical splicing disruption) that have been collectively reported in 15 probands in 7 publications (PMID: 26720455, PMID: 26355662, PMID: 39672920, PMID: 35892439, PMID: 27764769, PMID: 27842159, and PMID: 38078364). Overall, the variant types suggest that the mechanism of pathogenicity is loss of function.
This gene-disease relationship is also supported by multiple forms of experimental evidence, including biochemical studies indicating that AGBL5 encodes an enzyme (also known as CCP5) that is responsible for deglutamylating tubulin (PMID: 24022482). Mouse models of Agbl5 loss show disruption of this post-translational modification in the retinal cilia and recapitulate the abnormal retinal morphology in human probands (PMID: 39528655).
In conclusion, AGBL5 has a Definitive association with AGBL5-related retinopathy. This classification has been clearly demonstrated in both research and diagnostic settings and has been upheld over time without the emergence of conflicting evidence. This classification was approved by the Retina GCEP on March 6th, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.