PRPH2
protein-codingperipherin 2, the group of Tetraspanins
Gene summary
The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It may function as an adhesion molecule involved in stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. This protein is essential for disk morphogenesis. Defects in this gene are associated with both central and peripheral retinal degenerations. Some of the various phenotypically different disorders are autosomal dominant retinitis pigmentosa, progressive macular degeneration, macular dystrophy and retinitis pigmentosa digenic. [provided by RefSeq, Jul 2008]
- RP7
- RDS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~26.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011979
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0020381
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015993
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0020382
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013137
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011974
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:1040055
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:1040055
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0019118
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:1040055
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008982
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013137
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018877
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011974
Submitter: G2P
Inheritance Pattern: SD
Disease ID:MONDO:0011974
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011974
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007639
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:1040055
Submitter: ClinGen
The *PRPH2* gene was first reported in relation to autosomal dominant retinitis pigmentosa in 1991 (PMID: 1749427, PMID: 1684223). Subsequent publications expanded the phenotypic spectrum associated with heterozygous *PRPH2* variants to include diverse diagnoses such as central areolar choroidal dystrophy 2 (PMID: 7493155), patterned macular dystrophy 1 (PMID: 8485574), vitelliform macular dystrophy 3 (PMID: 9338584), retinitis punctata albescens (PMID: 8485575), and Stargardt macular dystrophy (PMID: 8111389). These cases collectively exhibit a wide variety of ophthalmic features ranging from nyctalopia, reduced visual acuity, and decreased light- and dark-adapted electroretinogram (ERG) amplitudes to choroidal neovascularization, macular pattern dystrophy, and/or yellow deposits at the level of the retinal pigment epithelium. The spectrum of disease also includes cases with biallelic *PRPH2* variants diagnosed as Leber congenital amaurosis 18 (PMID: 26061163) or juvenile retinitis pigmentosa (PMID: 23847139). These biallelic cases exhibit earlier onset and phenotypes such as reduced visual acuity, undetectable ERG responses, nystagmus, attenuation of retinal blood vessels, reduced macular thickness, patchy atrophy of the retinal pigment epithelium, and subretinal deposits. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (*PRPH2* loss of function) was found to be consistent among dominant and recessive cases of retinitis pigmentosa 7 (MIM#: 608133), central areolar choroidal dystrophy 2 (MIM#: 13105), patterned macular dystrophy 1 (MIM#: 169150), vitelliform macular dystrophy 3 (MIM#: 608161), retinitis punctata albescens (MIM#: 136880), and Leber congenital amaurosis (MIM#: 608133). The phenotypic variability between these diagnoses appears to represent a spectrum of disease rather than separate disease entities, with some families including affected individuals receiving different diagnoses and/or exhibiting different modes of inheritance (PMID: 26061163, PMID: 31618092). Therefore, cases carrying disease-causing *PRPH2* variants have been lumped into a single disease entity, referred to as PRPH2-related retinopathy, with a semidominant mode of inheritance. Eight suspected disease-causing variants were scored as part of this curation (one nonsense, three frameshift, three missense, and one short in-frame deletion); these have been collectively reported in nine probands in seven publications (PMID: 1749427, PMID: 1684223, PMID: 8485575, PMID: 8485576, PMID: 8251014, PMID: 7710395, PMID: 8111389, PMID: 26061163, PMID: 23847139). Five of the probands scored in this curation carried single heterozygous disease-associated variants within the *PRPH2* locus, while the other two probands carried biallelic *PRPH2* disease-associated variants. The molecular mechanism appears to include PRPH2 haploinsufficiency and biallelic loss of PRPH2 function (conferred by null and/or hypomorphic variants). It is not yet clear whether this loss-of-function mechanism is shared by all disease-causing variants and mouse studies suggest that some heterozygous missense variants may have dominant negative effects (PMID: 11978760, PMID: 15254014, PMID: 25167981, PMID: 35344225). Interestingly, some variants such as the c.554T>C (p.Leu185Pro) change appear to be associated with incomplete penetrance in the heterozygous state, and many of the heterozygous carriers from families with biallelic cases appear to be sub-clinically affected (PMID: 23847139). It is noted that the variant has also been observed in affected individuals believed to be linked to a digenic mode of inheritance, when it is encountered in heterozygous state together with a heterozygous presumed loss-of-function variant in the *ROM1* gene (PMID: 8202715). However, these cases have not been considered in the present curation. Two families with segregation evidence contributed to the scoring of the gene-disease relationship (PMID: 1749427, PMID: 1684223). The literature included more case-level and co-segregation evidence, but its inclusion in this curation was not necessary to reach the maximum score for genetic evidence. This gene-disease association is also supported by experimental evidence indicating that dysgenesis of the photoreceptor outer segment discs may be the shared defect underlying PRPH2-related disease. *PRPH2* is specifically expressed in retinal tissues (PMID: 30239781) and the protein product localizes particularly to the retinal outer segments (PMID: 1992463). Wild-type *Prph2* expression in the developing mouse retina begins on day postnatal day 6, coinciding with the formation of the photoreceptor outer segment discs, and is consistent with the idea that PRPH2 functions as an adhesion molecule that stabilizes these structures. PRPH2 protein physically interacts and forms a complex with the protein product of the *ROM1* gene (PMID: 8202715). PRPH2 and ROM1 co-localize within the rim regions of outer segment discs in the mouse retina (PMID: 25001182). A naturally occurring mouse model with homozygous loss-of-function variants within the *Prph2* locus shows progressive degeneration of the retina, absence of rods (PMID: 705766, PMID: 419532), abnormal development of photoreceptor outer segments, gradual photoreceptor degeneration (PMID: 2918924), and ERG recordings with completely extinguished responses (PMID: 6483282). A second mouse model with a heterozygous knock-in of the c.422A>G (p.Tyr141Cys) variant into the *Prph2* locus recapitulates human patient features such as photoreceptor outer segment loss, decreased rod ERG response, yellow retinal flecks in the fundus and abnormal high molecular weight complexes containing Prph2 (PMID: 25001182). In summary, *PRPH2* is definitively associated with PRPH2-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 was approved by the ClinGen Retina Gene Curation Expert Panel on February 1st, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0018998
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0024561
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0020242
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
Intervention: General
Rationale: Digenic inheritance (with ROM1) has been reported; 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 PRPH2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000322.5. 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 | 7 | 90 | 99 | |
| missense | 26 | 143 | 227 | 14 | 3 | 413 |
| nonsense | 50 | 23 | 1 | 74 | ||
| start loss | 4 | 2 | 6 | |||
| frameshift | 106 | 46 | 2 | 154 | ||
| splice donor/acceptor (+/-2bp) | 9 | 5 | 1 | 15 | ||
| Total | 196 | 220 | 238 | 104 | 3 | 761 |
Highest pathogenic variant AF is 0.00008611834
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000313.2 | 3 | MANE Select | |
| Ensembl | ENSP00000230381.5 | 3 | MANE Select | |
| Ensembl | ENSP00000802009.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- cell adhesion
- cell surface receptor signaling pathway
- visual perception
- retina development in camera-type eye
Cellular Component
- photoreceptor outer segment
- integral component of plasma membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000230381
- Coding exons
- 3
- Length
- 25973
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125748
- p
- 0.0000596
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.102 | 189 | 193 | 0.979 | 0.0000127 | 2273 |
| Missense (PolyPhen) | 39 | 49.852 | 0.78232 | 561 | ||
| Synonymous | -0.392 | 92 | 87.3 | 1.05 | 0.00000656 | 681 |
| Loss of Function | 2.44 | 4 | 13.8 | 0.291 | 7.39e-7 | 145 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.000079 | 0.000062 | rare |
| South Asian | 0.000098 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May function as an adhesion molecule involved in stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. It is essential for disk morphogenesis.;
- Disease
- DISEASE: Retinitis punctata albescens (RPA) [MIM:136880]: A form of fleck retina disease characterized by aggregation of white flecks posteriorly in the retina, causing night blindness and delayed dark adaptation. It differs from fundus albipunctatus in being progressive and evolving to generalized atrophy of the retina. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular dystrophy, vitelliform, 3 (VMD3) [MIM:608161]: A form of vitelliform macular dystrophy, a retinal disease characterized by yellow, lipofuscin-containing deposits, usually localized at the center of the macula. Patients usually become symptomatic in the fourth or fifth decade of life with a protracted disease of decreased visual acuity. {ECO:0000269|PubMed:15370544, ECO:0000269|PubMed:17653047, ECO:0000269|PubMed:20213611, ECO:0000269|PubMed:26796962, ECO:0000269|PubMed:9338584}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular dystrophy, patterned, 1 (MDPT1) [MIM:169150]: A form of retinal patterned dystrophy, a heterogeneous group of macular disorders that includes reticular (fishnet-like) dystrophy, macroreticular (spider-shaped) dystrophy and butterfly- shaped pigment dystrophy. {ECO:0000269|PubMed:16024869, ECO:0000269|PubMed:26796962, ECO:0000269|PubMed:8485574, ECO:0000269|PubMed:9443872}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Choroidal dystrophy, central areolar 2 (CACD2) [MIM:613105]: A form of central areolar choroidal dystrophy, a retinal disease that affects the macula and results in a well- demarcated circumscribed area of atrophy of the pigment epithelium and choriocapillaris. {ECO:0000269|PubMed:16832026, ECO:0000269|PubMed:19038374, ECO:0000269|PubMed:20213611, ECO:0000269|PubMed:26796962}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in PRPH2 are found in different retinal diseases including cone-rod dystrophy, retinitis pigmentosa, macular degeneration. The mutations underlying autosomal dominant retinitis pigmentosa and severe macular degeneration are largely missense or small in-frame deletions in a large intradiscal loop between the third and fourth transmembrane domains. In contrast, those associated with the milder pattern phenotypes or with digenic RP are scattered more evenly through the gene and are often nonsense mutations. This observation correlates with the hypothesis that the large loop is an important site of interaction between PRPH2 molecules and other protein components in the disk.;
Recessive Scores
- pRec
- 0.214
Intolerance Scores
- LoFtool
- 0.171
- RVIS EVS
- 0.46
- RVIS percentile EVS
- 78.59
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.134
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |