PDE6C
protein-codingphosphodiesterase 6C, the group of Phosphodiesterases
Gene summary
This gene encodes the alpha-prime subunit of cone phosphodiesterase, which is composed of a homodimer of two alpha-prime subunits and 3 smaller proteins of 11, 13, and 15 kDa. Mutations in this gene are associated with cone dystrophy type 4 (COD4). [provided by RefSeq, Mar 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~53.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0000455
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013129
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013129
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013129
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:1040028
Submitter: ClinGen
The *PDE6C* gene was first reported in relation to cone dystrophy with an autosomal recessive mode of inheritance in 2009 (Thiadens et al., PMID: 19615668). Affected individuals with biallelic causal variants in *PDE6C* have since been identified in a number of subsequent publications. Phenotypes generally occur with congenital or early childhood onset and include severe color vision defects, progressive loss of visual acuity over the course of decades, reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus. At least one patient has been reported with central scotoma and macular retinal pigment epithelium atrophy (PMID: 19887631). These cases with causal variants in *PDE6C* are specifically described as cone dystrophy 4 or achromatopsia 5 (MIM#: 613093), depending on the extent of disease progression at the time of diagnosis. Additional case reports have suggested an expanded spectrum of disease that includes phenotypes consistent with cone-rod dystrophy, including electroretinograms with decreased amplitude on both phototopic and scotopic waveforms and mild/moderate constrictions to visual field (PMID: 33001157). Because these diagnoses are considered part of the same phenotypic spectrum, this curation has evaluated a combination of cases under the disease term PDE6C-related retinopathy. Thirteen suspected deleterious variants in *PDE6C* were scored as part of this curation (five nonsense, 1 frameshift, four missense, and three affecting splicing). These variants have been collectively reported in eight probands in three publications (PMID: 19615668, PMID: 19887631, PMID: 30080950). Three probands were homozygous for the variant of interest, but were not reported to be members of consanguineous families. The mechanism of pathogenicity appears to be loss of function in *PDE6C*, characterized in at least some cases by variants predicted to trigger the absence of the gene product or loss of the majority of its enzymatic activity. Additional genetic evidence was available (PMID: 32306724, PMID: 33001157, PMID: 37433860) but not included in this curation as the maximum scoring for this evidence type had already been reached. This gene-disease association is also supported by evidence that *PDE6C* is highly expressed specifically in retinal tissues (PMID: 30239781). Biochemical data show that *PDE6C* encodes a cGMP phosphodiesterase that is part of the phototransduction cascade and is associated specifically with cone photoreceptor cells, consistent with the cone-specific dysfunction observed in the human patients (PMID: 19801642). This biochemical function parallels that of the *PDE6A* gene, which encodes a rod-specific cGMP phosphodiesterase and harbors loss-of-function variants associated with retinal dystrophy (PMID: 7493036). Naturally occurring zebrafish, mice, and rhesus macaque models harboring biallelic loss-of-function variants in the gene orthologous to *PDE6C* recapitulate many of the features of the human patients such as reduced visual acuity, particularly under normal lighting conditions, lack of light-adapted ERG responses, and normal dark-adapted ERG responses (PMID: 18824093, PMID: 19887631, PMID: 30667376). These models also collectively exhibit progressive thinning of the outer nuclear layer and photoreceptor outer segments within the macula, caused by rapid and progressive loss of cone photoreceptors (PMID: 18824093, PMID: 19887631, PMID: 30667376). In summary, *PDE6C* is definitively associated with PDE6C-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification has been approved by the ClinGen Retina GCEP on November 2nd, 2023 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0013129
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0018852
Submitter: Orphanet
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 PDE6C variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006204.4. 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 | 1 | 8 | 156 | 166 | |
| missense | 7 | 35 | 311 | 23 | 1 | 377 |
| nonsense | 9 | 11 | 20 | |||
| start loss | 0 | |||||
| frameshift | 25 | 16 | 41 | |||
| splice donor/acceptor (+/-2bp) | 7 | 20 | 1 | 28 | ||
| Total | 49 | 83 | 320 | 179 | 1 | 632 |
Highest pathogenic variant AF is 0.00003780278
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006195.3 | 22 | MANE Select | |
| Ensembl | ENSP00000360502.3 | 22 | MANE Select | |
| Ensembl | ENSP00000809876.1 | 22 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pde6c | Danio rerio | Structure: ON-bipolar cell Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Purine metabolism - Homo sapiens (human)
- Phosphodiesterases in neuronal function
- Purine metabolism
- Purine nucleotides nucleosides metabolism
- Visual signal transduction: Cones
Biological Process
- visual perception
- phototransduction, visible light
- retinal cone cell development
Molecular Function
- cGMP binding
- metal ion binding
- 3',5'-cyclic-GMP phosphodiesterase activity
Cellular Component
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371447
- Coding exons
- 22
- Length
- 53423
- Individuals with no LoFs
- 125669
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 79
- Defined
- 125748
- p
- 0.000314
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.14 | 387 | 455 | 0.850 | 0.0000242 | 5716 |
| Missense (PolyPhen) | 142 | 196.23 | 0.72365 | 2518 | ||
| Synonymous | -1.31 | 190 | 168 | 1.13 | 0.00000966 | 1535 |
| Loss of Function | 2.33 | 33 | 51.0 | 0.647 | 0.00000277 | 601 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00049 | 0.00049 | rare |
| Latino/Admixed American | 0.00064 | 0.00064 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00023 | 0.00023 | rare |
| South Asian | 0.00049 | 0.00049 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: As cone-specific cGMP phosphodiesterase, it plays an essential role in light detection and cone phototransduction by rapidly decreasing intracellular levels of cGMP. {ECO:0000269|PubMed:21127010, ECO:0000269|PubMed:28583373}.;
- Disease
- DISEASE: Cone dystrophy 4 (COD4) [MIM:613093]: An early-onset cone dystrophy. Cone dystrophies are retinal dystrophies characterized by progressive degeneration of the cone photoreceptors with preservation of rod function, as indicated by electroretinogram. However, some rod involvement may be present in some cone dystrophies, particularly at late stage. Affected individuals suffer from photophobia, loss of visual acuity, color vision and central visual field. Another sign is the absence of macular lesions for many years. Cone dystrophies are distinguished from the cone-rod dystrophies in which some loss of peripheral vision also occurs. {ECO:0000269|PubMed:19615668}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Achromatopsia 5 (ACHM5) [MIM:613093]: A form of achromatopsia, an ocular stationary disorder due to the absence of functioning cone photoreceptors in the retina. It is characterized by total colorblindness, low visual acuity, photophobia and nystagmus. ACHM5 inheritance is autosomal recessive. {ECO:0000269|PubMed:19615668, ECO:0000269|PubMed:21127010, ECO:0000269|PubMed:28583373}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.133
Intolerance Scores
- LoFtool
- 0.816
- RVIS EVS
- 0.12
- RVIS percentile EVS
- 62.17
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.189
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |