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ADGRV1
adhesion G protein-coupled receptor V1
ADGRV1 encodes a large adhesion G protein-coupled receptor critical for sensory function in the inner ear and retina. The ADGRV1 gene provides instructions for making a very large protein that belongs to the adhesion G protein-coupled receptor family.
ADGRV1 is located on the long (q) arm of chromosome 5, at band 5q14.3. Arm ratio per GRCh38 - banding schematic.
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Overview
ADGRV1 (adhesion G protein-coupled receptor V1) is located on chromosome 5q14.3 and encodes one of the largest known G protein-coupled receptors in humans. The protein is particularly abundant in the sensory hair cells of the inner ear and the photoreceptor cells of the retina, where it contributes to the structural organisation and function of specialised cellular projections. Pathogenic variants in ADGRV1 are associated with both syndromic and non-syndromic forms of hearing loss, reflecting the protein's critical role in auditory function. The gene is included in NHS clinical genomics panels for both hearing loss and retinal disorders, underscoring its importance in inherited sensory conditions.
What the gene does
The ADGRV1 protein functions as an adhesion G protein-coupled receptor, combining features of cell adhesion molecules with the signalling capacity of GPCRs. In the inner ear, the protein localises to the ankle links and stereocilia of cochlear hair cells, where it helps maintain the structural integrity of these mechanosensory projections that convert sound vibrations into electrical signals. The protein's large extracellular region likely participates in cell-cell or cell-matrix interactions, whilst its seven-transmembrane domain enables signal transduction across the cell membrane. In retinal photoreceptor cells, ADGRV1 is found in the connecting cilium and periciliary membrane complex, regions essential for the transport of proteins between the inner and outer segments of these light-detecting cells. The protein appears to work in coordination with other Usher syndrome proteins to form functional networks that support sensory cell architecture and survival.
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Chromosome location
ADGRV1 is located on the long arm of chromosome 5 at position 14.3 (5q14.3). The gene spans a substantial genomic region and contains 90 exons, reflecting the large size of the encoded protein. The chromosomal region 5q14.3 is not associated with recurrent structural rearrangements, and pathogenic changes in ADGRV1 typically arise from sequence-level variants rather than deletions or duplications.
Protein structure
The ADGRV1 protein comprises 6,306 amino acids, making it one of the longest human proteins. The extracellular region contains 15 Calx-beta domains (Calx-beta 1 through Calx-beta 15), spanning from amino acids 30 to 2206. These calcium-binding domains are thought to participate in protein-protein interactions and may respond to local calcium concentrations in sensory cells. Following the extensive Calx-beta repeat region, the protein contains a GPCR proteolytic site (GPS domain) and a characteristic seven-transmembrane domain typical of G protein-coupled receptors, enabling the protein to transduce extracellular signals to intracellular pathways. The intracellular C-terminal region contains motifs that likely interact with scaffolding proteins and signalling molecules within hair cells and photoreceptors.
Key variants
Pathogenic variants in ADGRV1 are distributed across the gene's 90 exons, with both missense and truncating variants reported. Loss-of-function variants generally lead to more severe phenotypes, whilst some missense changes in specific functional domains may result in milder or tissue-restricted presentations. The inheritance pattern varies depending on the associated condition: Usher syndrome type 2C follows an autosomal recessive pattern, whilst some forms of non-syndromic hearing loss may also demonstrate recessive inheritance.
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.10054-1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.10088_10091del | p.Val3363fs | Pathogenic | ★★☆☆ | Retinal dystrophy |
c.10213C>T | p.Arg3405Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.10458G>A | p.Trp3486Ter | Pathogenic | ★★☆☆ | Usher syndrome type 2 |
c.10476_10479del | p.Phe3493fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1055C>T | p.Pro352Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive sensorineural hearing loss |
c.10736_10737del | p.Ala3579fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.10935_10938del | p.Ser3646fs | Pathogenic | ★★☆☆ | not provided |
c.11410C>T | p.Arg3804Ter | Pathogenic | ★★☆☆ | not provided |
c.11547_11550del | p.Ile3849fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
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 ADGRV1 are primarily associated with Usher syndrome type 2C, characterised by moderate to severe hearing loss from birth and progressive vision loss due to retinitis pigmentosa that typically begins in adolescence or early adulthood. Unlike Usher syndrome type 1, individuals with type 2 generally retain normal balance function. Variants in ADGRV1 can also cause non-syndromic hearing loss affecting only auditory function without retinal involvement, although this appears to be less common than the syndromic presentation.
No disease links recorded for this gene in our reference set.
UK clinical status
ADGRV1 is listed on multiple NHS Genomic Medicine Service gene panels. It appears on the Monogenic hearing loss panel (version R67, green classification) and the Retinal disorders panel (version R32, green classification). Green classification indicates strong evidence supporting the gene-disease relationship and its use in diagnostic testing within the NHS. These panel inclusions reflect the gene's established role in both auditory and visual sensory disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What type of protein does ADGRV1 encode?
ADGRV1 encodes an adhesion G protein-coupled receptor, a specialised protein that combines cell adhesion properties with the ability to transmit signals across the cell membrane. It is one of the largest known GPCRs in the human genome.
Why does ADGRV1 affect both hearing and vision?
The ADGRV1 protein is expressed in both cochlear hair cells of the inner ear and photoreceptor cells of the retina, where it supports the structural and functional integrity of specialised sensory projections. Pathogenic variants can therefore impair both auditory and visual function, leading to Usher syndrome.
Are all ADGRV1 variants associated with vision loss?
No, some ADGRV1 variants cause non-syndromic hearing loss without affecting vision. The specific type and location of the variant, along with other genetic and environmental factors, influence whether a person develops isolated hearing loss or the combined hearing and vision problems characteristic of Usher syndrome.