IMPG2
protein-codinginterphotoreceptor matrix proteoglycan 2
Gene summary
The protein encoded by this gene binds chondroitin sulfate and hyaluronan and is a proteoglycan. The encoded protein plays a role in the organization of the interphotoreceptor matrix and may promote the growth and maintenance of the light-sensitive photoreceptor outer segment. Defects in this gene are a cause of retinitis pigmentosa type 56 and maculopathy, IMPG2-related.[provided by RefSeq, Mar 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~98.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013314
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011979
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013314
Submitter: G2P
Inheritance Pattern: Unknown
Disease ID:MONDO:0014509
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014509
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0700241
Submitter: ClinGen
The *IMPG2* gene was first reported in relation to ocular disease in 2010, in affected members of two families who were diagnosed with retinitis pigmentosa with autosomal recessive inheritance (PMID: 20673862). The known spectrum of recessive disease continued to expand with reports of individuals affected with retinitis pigmentosa with relatively early macular involvement (PMID: 24876279) or rod-cone dystrophy (PMID: 31264916). *IMPG2* variants were subsequently identified as the basis for autosomal dominant inheritance of vitelliform macular dystrophy (PMID: 25085631), raising the question of whether this disease entity is distinct from retinitis pigmentosa or whether they can occur within the same families. Cases diagnosed with retinitis pigmentosa 56 generally exhibit features such as night blindness, progressive visual loss, macular retinal pigment epithelium (RPE) mottling / atrophy, decreased ERG amplitudes (affecting rods more severely than cones), color vision defect, peripheral visual field loss, central scotoma, retinal blood vessel attenuation, and/or optic disc pallor. These features are largely distinct from the vitelliform macular dystrophy phenotypes, which include foveal vitelliform lesions, dome-shaped foveal detachment with material above the RPE, normal to mildly decreased visual acuity, normal or decreased amplitude ERG responses, and central RPE atrophy. The two disease entities strongly correlate with mode of inheritance, so that biallelic loss-of-function consistently associates with retinitis pigmentosa, while monoallelic loss-of-function consistently associates with vitelliform macular dystrophy. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (monoallelic vs. biallelic *IMPG2* loss of function) and mode of inheritance (autosomal dominant vs. autosomal recessive) appear to be distinct between patients with vitelliform macular dystrophy 5 (MIM# 616152) or retinitis pigmentosa 56 (MIM# 613581). Therefore, cases caused by inherited *IMPG2* variants have been split into two separate disease entities. The present curation has focused on autosomal recessive cases and is referred to as IMPG2-related recessive retinopathy. Ten suspected disease-causing variants were scored as part of this curation (five nonsense, one frameshift, one canonical splice site disruption, one in-frame exon deletion, and two missense). These variants have been collectively reported in eight probands in four publications (PMID: 24876279, PMID: 20673862, PMID: 31264916, PMID: 34990796). All eight of the probands scored in this curation harbored two variant alleles within the *IMPG2*. The mechanism of pathogenicity appears to be biallelic loss of *IMPG2* function conferred by null and/or hypomorphic variants. Three families with segregation evidence contributed to the scoring of the gene-disease relationship (PMID: 24876279). Additional genetic evidence was available but was not necessary to include in this curation, as the maximum for this category of evidence had already been reached. This gene-disease association is also supported by biochemical evidence that *IMPG2* encodes a component of the interphotoreceptor matrix (PMID: 10542133), an insoluble extracellular layer located between the retinal pigment epithelium and the neural retina that is known to support the function and maintenance of photoreceptor cells (PMID: 7344830). The *IMPG2* gene similarly encodes a component of this structure (PMID: 10601738) and harbors variants associated with vitelliform macular dystrophy 4 and retinitis pigmentosa 91 (PMID: 23993198), PMID: 32817297). Gene expression profiling across human tissues shows that *IMPG2* mRNA levels are at their highest in retinal tissues (PMID: 30239781). Zebrafish with morpholino-based *Impg2* silencing exhibit decreased cone and rod photoreceptor outer segment length (PMID: 32817297). Mouse models with homozygous CRISPR/Cas9-based *Impg2* disruption exhibit a phenotype with features of human retinitis pigmentosa and vitelliform macular dystrophy, including development of subretinal hyper-reflective vitelliform lesions, mislocalization of Impg1, reduction in the amplitudes of rod and cone ERG responses (PMID: 32265257), disorganization of cone-specific markers, pigmentary retinopathy, and enhanced apoptosis / decreased thickness of the outer nuclear layer (PMID: 32242237). Finally, retinal organoids derived from a compound heterozygous patient exhibit defective development of both the inner photoreceptor matrix and outer segment, and can be rescued by correction of both *Impg2* alleles (PMID: 36206764). In summary, *IMPG2* is definitively associated with IMPG2-related recessive 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 August 3rd, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0013314
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014509
Submitter: PanelApp Australia
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 IMPG2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016247.4. 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 | 10 | 190 | 200 | |||
| missense | 1 | 16 | 560 | 24 | 1 | 602 |
| nonsense | 27 | 30 | 57 | |||
| start loss | 0 | |||||
| frameshift | 35 | 31 | 66 | |||
| splice donor/acceptor (+/-2bp) | 3 | 31 | 3 | 37 | ||
| Total | 66 | 108 | 573 | 214 | 1 | 962 |
Highest pathogenic variant AF is 0.00015872622
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057331.2 | 19 | MANE Select | |
| Ensembl | ENSP00000193391.6 | 19 | MANE Select |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- visual perception
Molecular Function
- extracellular matrix structural constituent
- hyaluronic acid binding
- heparin binding
Cellular Component
- integral component of membrane
- extracellular matrix
- interphotoreceptor matrix
- receptor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000193391
- Coding exons
- 19
- Length
- 98015
- Individuals with no LoFs
- 125682
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 66
- Defined
- 125748
- p
- 0.000262
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.207 | 641 | 626 | 1.02 | 0.0000312 | 8159 |
| Missense (PolyPhen) | 110 | 137.93 | 0.79751 | 1937 | ||
| Synonymous | -0.238 | 236 | 231 | 1.02 | 0.0000122 | 2372 |
| Loss of Function | 3.27 | 30 | 56.5 | 0.531 | 0.00000285 | 727 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00076 | 0.00076 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00028 | 0.00028 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Chondroitin sulfate- and hyaluronan-binding proteoglycan involved in the organization of interphotoreceptor matrix; may participate in the maturation and maintenance of the light- sensitive photoreceptor outer segment. Binds heparin. {ECO:0000269|PubMed:10702256}.;
- Disease
- DISEASE: Retinitis pigmentosa 56 (RP56) [MIM:613581]: 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:20673862}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular dystrophy, vitelliform, 5 (VMD5) [MIM:616152]: A form of macular dystrophy, a retinal disease in which various forms of deposits, pigmentary changes, and atrophic lesions are observed in the macula lutea. Vitelliform macular dystrophies are characterized by yellow, lipofuscin-containing deposits, usually localized at the center of the macula. VMD5 features include late- onset moderate visual impairment and preservation of retinal pigment epithelium reflectivity. {ECO:0000269|PubMed:20673862, ECO:0000269|PubMed:25085631}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.113
Intolerance Scores
- LoFtool
- 0.864
- RVIS EVS
- -0.84
- RVIS percentile EVS
- 11.45
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.112
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |