REEP6
protein-codingreceptor accessory protein 6, the group of Receptor accessory proteins
Gene summary
The protein encoded by this gene may be involved in the transport of receptors from the endoplasmic reticulum (ER) to the cell surface. The encoded protein may also play a role in regulating ER membrane structure. This gene is required for the proper development of retinal rods and photoreceptors, with defects in this gene being associated with retinitis pigmentosa 77. [provided by RefSeq, May 2017]
- C19orf32
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019200
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0015013
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0015013
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0019118
Submitter: ClinGen
The *REEP6* gene was first reported in relation to retinitis pigmentosa 77 with an autosomal recessive inheritance in 2016 (Arno et al., PMID: 27889058). Affected individuals with causal variants in *REEP6* have since been identified in 3 other publications (PMID: 29120066, 31538292 and 33917198), with cases showing onset at ages ranging from early childhood to 39 years. Presenting phenotypes include a combination of nyctalopia, bony spicules, constricted visual fields, reduced visual acuity, attenuated retinal vessels, severe generalized retinal dystrophy with severely reduced or undetectable electroretinogram (ERG) responses and outer retinal atrophy. Additional features can include cystoid macular edema, posterior subcapsular cataracts and dyschromatopsia. These cases with causal variants in *REEP6* are typically diagnosed with retinitis pigmentosa 77 (MONDO:0015013, MIM #: 617304), but have been curated under the broader disease term REEP6-related retinopathy in order to be inclusive of the full diversity of patient phenotypes. This curation has scored ten suspected deleterious variants in *REEP6* (four missense, four frameshift, one nonsense and one canonical splice site), which have been collectively reported in nine probands in four publications (PMIDs: 27889058, 29120066, 31538292 and 33917198). Most of the probands were members of consanguineous families and were homozygous for the variant of interest. The mechanism of pathogenicity appears to be loss of function in REEP6, characterized in at least some cases by variants predicted to trigger the absence of the gene product. More genetic evidence is available in the literature, but the maximum score for genetic evidence has been reached (PMID: 36819107). This gene-disease association is also supported by expression evidence that the long isoform (*REEP6.1*) of *REEP6* is highly expressed in the retina, specifically in rod photoreceptors (PMIDs: 34104971 and 24691551). Biochemical studies further support a structural function of REEP6 in the retina as evidenced by strong binding of NRL (associated with retinal degeneration and retinitis pigmentosa 27) in the intronic region of *REEP6*, which increases its promoter activity in an *in vitro* reporter assay (PMID: 24691551). Furthermore, REEP6 is present in a subset of clathrin-coated vesicles (STX3) and colocalizes in rod spherules. This study suggests a critical function of REEP6 in trafficking of cargo via a subset of clathrin-coated vesicles to selected membrane sites in rod photoreceptor cells (28369466). Knockdown of *Reep6* in mouse retina using shRNA might lead to the death of transfected photoreceptor cells as shown by thinner outer nuclear layer in the electroporated area. Knockdown of reep6 by translation blocking morpholino in zebrafish leads to severely compromised eye development in the morphants. Taken together, these results show that *REEP6* is required for retinal development in zebrafish and mouse (24691551). *Reep6L135P/-* compound heterozygous mice mimic the patient genotype and recapitulate the early-onset retinal degeneration phenotypes observed in the individual with retinitis pigmentosa. rAAV-mediated *REEP6* transduction in photoreceptor cells successfully rescued the phenotypes including thin outer nuclear layer and rod ERG responses (PMIDs: 30101608 and 34104971). In summary, *REEP6* is definitively associated with REEP6-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 July 11th, 2024 (SOP Version 10).
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 REEP6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_138393.4. 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 | 2 | 61 | 2 | 65 | ||
| missense | 1 | 3 | 108 | 8 | 1 | 121 |
| nonsense | 3 | 3 | 1 | 7 | ||
| start loss | 1 | 1 | 1 | 3 | ||
| frameshift | 5 | 3 | 8 | |||
| splice donor/acceptor (+/-2bp) | 2 | 5 | 7 | |||
| Total | 12 | 15 | 112 | 69 | 3 | 211 |
Highest pathogenic variant AF is 0.00007881332
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_612402.1 | 5 | MANE Select | |
| Ensembl | ENSP00000233596.2 | 5 | MANE Select | |
| RefSeq | NP_001316485.1 | 6 | MANE Plus Clinical | |
| Ensembl | ENSP00000378861.5 | 6 | MANE Plus Clinical |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| reep6 | Danio rerio | Structure: retina layer formation Quality: disrupted abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signaling by GPCR
- Signal Transduction
- Olfactory Signaling Pathway
- G alpha (s) signalling events
- GPCR downstream signalling
Biological Process
- regulation of intracellular transport
- detection of light stimulus involved in visual perception
Molecular Function
- protein binding
Cellular Component
- photoreceptor inner segment
- nucleus
- endoplasmic reticulum
- endoplasmic reticulum membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000233596
- Coding exons
- 5
- Length
- 6762
- Individuals with no LoFs
- 125391
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 17
- Defined
- 125408
- p
- 0.0000678
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.157 | 115 | 110 | 1.04 | 0.00000755 | 1155 |
| Missense (PolyPhen) | 39 | 37.667 | 1.0354 | 361 | ||
| Synonymous | 0.357 | 53 | 56.4 | 0.939 | 0.00000469 | 377 |
| Loss of Function | 0.470 | 8 | 9.57 | 0.836 | 5.09e-7 | 101 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00019 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May play a role in intracellular protein transport from the endoplasmic reticulum to the cell surface (By similarity). Required for correct function and survival of retinal photoreceptors (PubMed:27889058). {ECO:0000250|UniProtKB:Q9JM62, ECO:0000269|PubMed:27889058}.;
Recessive Scores
- pRec
- 0.0385
Intolerance Scores
- LoFtool
- 0.462
- RVIS EVS
- -0.43
- RVIS percentile EVS
- 25.15
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.763
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |