PDE6G
protein-codingphosphodiesterase 6G, the group of Phosphodiesterases
Gene summary
This gene encodes the gamma subunit of cyclic GMP-phosphodiesterase, which is composed of alpha- and beta- catalytic subunits and two identical, inhibitory gamma subunits. This gene is expressed in rod photoreceptors and functions in the phototransduction signaling cascade. It is also expressed in a variety of other tissues, and has been shown to regulate the c-Src protein kinase and G-protein-coupled receptor kinase 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2009]
- PDEG
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013315
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:1040034
Submitter: ClinGen
*PDE6G* was first reported in relation to retinitis pigmentosa 57, an autosomal recessive form of retinopathy, in 2010 (Dvir et al, PMID: 20655036). This is the only disorder known to be associated with *PDE6G* at the current time. The disease entity has been renamed as PDE6-related retinopathy. A canonical splice site variant shown by RT-PCR analysis to result in a frameshift has been reported in 6 homozygous affected individuals in an extended Israeli family of Muslim Arab origin (Dvir et al, 2010 PMID: 20655036). Affected individuals presented with early onset, severe disease. Two other apparently unrelated individuals have been reported (Van Schil et al, 2018, PMID: 28749477) with inherited retinal disease and homozygosity for the same copy number variant (GRCh37 chr17: g.79612525_79619171del, also denoted as NM_001290212.1(TSPAN10): c.658_NM_002602.3 (PDE6G):c.147-456del, which includes loss of coding exons 3 and 4 of *PDE6G*, and part of *TSPAN10*). Three unpublished probands and one affected sibling have been reported with retinopathy and homozygosity for the same frameshift variant, NM_002602.4:c.69dup, p.(Arg24GlnfsTer6) (Invitae, personal communication). Additional unpublished cases with homozygosity for loss of function variants are known to members of the ClinGen Retina GCEP. The cases reported in PMID: 28749477 and the unpublished cases could not be entered and scored in the GCI due to technical limitations. The disease mechanism appears to be loss of function. This gene-disease relationship is also supported by experimental evidence. A detailed review outlines extensive evidence supporting the function of PDE6G, a function that is consistent with the disease entity (Cote et al, 2022, PMID: 34170501). In brief, PDE6G encodes the gamma (inhibitory) subunit of rod-specific phosphodiesterase 6 (PDE6). PDE6 is a multi-subunit enzyme composed of alpha and beta catalytic subunits (PDE-alpha and PDE-beta, encoded by *PDE6A* and *PDE6B* respectively), and two inhibitory gamma subunits (PDE-gamma, encoded by *PDE6G*). PDE6 is an essential component of the visual transduction cascade. In response to light activation, PDE6 regulates intracellular cyclic guanosine monophosphate levels by hydrolysis of cyclic guanosine monophosphate (cGMP). The PDE-gamma subunit is a multi-functional regulator of PDE6 activity, and thus plays a critical role in vision (Power et al, 2019, PMID: 31374251). PDE-gamma interacts with the products of other genes which have been implicated in retinal dystrophy, including *PDE6A*, *PDE6B*, and *GNAT1* (Irwin et al, 2019, PMID: 31690623). The gene is most highly expressed in retina and retinal pigment epithelium with much lower expression in other tissues (Bryan et al, 2018, PMID: 30239781). In addition, two knock-out mouse models recapitulate the early onset, severe features of retinopathy observed in patients (Tsang et al, 1996, PMID: 8638127; Jentzsch et al, 2023, PMID: 37363133). The retinal degeneration phenotype in *Pde6g* knockout mice is rescued by expression of a wild type *Pde6g* transgene (Tsang et al, 1998, PMID: 9756475). Finally, functional alteration studies, in which different mutant *Pde6g* cDNAs were expressed in knockout mice, have helped to elucidate the functional domains of Pde6g and *in vivo* impact of different variants (Farber and Tsang, 2003, PMID: 12700134). As noted, due to technical limitations, some cases could not be scored in the GCI. However, even if these cases were scored conservatively, the total score would exceed 12 points. Therefore, there is definitive evidence supporting the relationship between *PDE6G* and PDE6G-related retinopathy (also known as retinitis pigmentosa 57). This classification was approved by the ClinGen Retina Gene Curation Expert panel on June 6th, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0013315
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013315
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013315
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PDE6G variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002602.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 22 | 23 | |||
| missense | 44 | 3 | 47 | |||
| nonsense | 1 | 1 | 2 | |||
| start loss | 1 | 1 | 2 | |||
| frameshift | 1 | 2 | 1 | 4 | ||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 4 | 3 | 48 | 25 | 0 | 80 |
Highest pathogenic variant AF is 0.000006572461
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002593.1 | 3 | MANE Select | |
| Ensembl | ENSP00000328412.5 | 3 | MANE Select | |
| RefSeq | NP_001352653.1 | 3 | Standard | |
| RefSeq | NP_001352654.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Purine metabolism - Homo sapiens (human)
- Phototransduction - Homo sapiens (human)
- Phosphodiesterases in neuronal function
- Signaling by GPCR
- Signaling by WNT
Biological Process
- activation of MAPK activity
- visual perception
- regulation of rhodopsin mediated signaling pathway
- negative regulation of catalytic activity
- positive regulation of epidermal growth factor receptor signaling pathway
Molecular Function
- enzyme inhibitor activity
- protein binding
- spectrin binding
- cGMP binding
- 3',5'-cyclic-GMP phosphodiesterase activity
Cellular Component
- plasma membrane
- photoreceptor disc membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000331056
- Coding exons
- 3
- Length
- 12654
- Individuals with no LoFs
- 124529
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 124535
- p
- 0.0000241
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0272 | 50 | 49.5 | 1.01 | 0.00000250 | 561 |
| Missense (PolyPhen) | 23 | 25.157 | 0.91427 | 287 | ||
| Synonymous | 0.0351 | 19 | 19.2 | 0.990 | 9.92e-7 | 171 |
| Loss of Function | 0.571 | 3 | 4.27 | 0.702 | 1.83e-7 | 48 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Participates in processes of transmission and amplification of the visual signal. cGMP-PDEs are the effector molecules in G-protein-mediated phototransduction in vertebrate rods and cones.;
- Disease
- DISEASE: Retinitis pigmentosa 57 (RP57) [MIM:613582]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:20655036}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.134
Intolerance Scores
- LoFtool
- 0.603
- RVIS EVS
- 0.19
- RVIS percentile EVS
- 66.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.867
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |