GeneBe

IMPDH1

protein-coding

inosine monophosphate dehydrogenase 1

Gene summary

The protein encoded by this gene acts as a homotetramer to regulate cell growth. The encoded protein is an enzyme that catalyzes the synthesis of xanthine monophosphate (XMP) from inosine-5'-monophosphate (IMP). This is the rate-limiting step in the de novo synthesis of guanine nucleotides. Defects in this gene are a cause of retinitis pigmentosa type 10 (RP10). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

Previous symbols:
  • RP10

MANE transcript

NM_000883.4

Inheritance

AD

ClinVar variants

P:49U:313B:177

Top phenotype

Retinitis pigmentosa 10; Leber congenital amaurosis 11

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr7:128,392,277-128,409,986

External References & Databases

Ensembl (ENSG00000106348)NCBI Gene (3614)OMIM (146690)HGNC:6052GenCCUniProt (P20839)AlphaFoldClinVar (IMPDH1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~17.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leber congenital amaurosis 11LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013454

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 10DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008379

Submitter: G2P

retinitis pigmentosa 10MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008379

Submitter: Ambry Genetics

retinitis pigmentosa 10STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008379

Submitter: Labcorp Genetics (formerly Invitae)

Leber congenital amaurosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018998

Submitter: Orphanet

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

IMPDH1-related retinopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1040051

Submitter: ClinGen

Variants in the *IMPDH1* gene were first identified as the cause of autosomal dominant cases of retinitis pigmentosa 10 (MIM#: 180105) in 2002 (PMID: 11875050) and account for ~2-3% of all retinitis pigmentosa cases (PMID: 37259572). Disease-causing IMPDH1 variants reportedly have dominant negative effects, consistent with the observation that *Impdh1* knock-out mice exhibit only a mild retinopathy (PMID: 14981049). *IMPDH1* variants have also been asserted in relation to autosomal dominant cases of Leber congenital amaurosis 11 (PMID: 16384941). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal dominant) and molecular mechanism (monoallelic dominant negative *IMPDH1* variants) have been found to be consistent among patients diagnosed with either retinitis pigmentosa 10 (MIM# 180105) or Leber congenital amaurosis 11 (MIM# 613837), while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *IMPDH1* variants have been lumped into a single disease entity, referred to as IMPDH1-related retinopathy. At least 10 *IMPDH1* variants (9 missense changes and 1 in-frame deletion of a single amino acid) have been associated with autosomal dominant retinitis pigmentosa or Leber congenital amaurosis. These forms of IMPDH1-related retinopathy generally present with night blindness and visual field constriction that progress gradually to loss of central vision (PMID: 11875050, PMID: 11875049, PMID: 34813793, PMID: 15851576, PMID: 37259572). Two recurrent variants, c.926G>C (p.Arg309Pro) and c.676G>A, (p.Asp226Asn), have been reported in numerous affected individuals (PMID: 37259572). This curation has collected data from 17 individuals and 2 families with 17 unique variants (PMID: 11875049, PMID: 11875050, PMID: 34813793, PMID: 15851576, PMID: 37259572). This gene-disease relationship is also supported by experimental evidence in the form of expression, biochemical function, animal modelling and function alteration data linking the *IMPDH1* gene and its protein product to retinal disease (PMID: 14981049, PMID: 11875049, PMID: 34813793). *IMPDH1* (inosine monophosphate dehydrogenase 1) encodes a critical enzyme involved in the generation of the purine base guanine (PMID: 11875049; PMID: 37259572). Despite the housekeeping function of IMPDH1, it is expressed at higher levels in the retina, which is an energy-demanding tissue that requires high generation of both ATP and GTP. The IMPDH1 protein supplies GTP to photoreceptor cells and is allosterically regulated based on changes in illumination to control GTP availability (PMID: 14981049, PMID: 34813793, PMID: 37259572). In summary, *IMPDH1* is definitively associated with autosomal dominant IMPDH1-related retinopathy This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of conflicting evidence. This clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel on February 1st, 2024 (SOP version 10).

IMPDH1-related retinopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:1040051

Submitter: PanelApp Australia

Leber congenital amaurosis 11DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013454

Submitter: G2P

Clinical Genomic Database (CGD)

Retinitis pigmentosa 10; Leber congenital amaurosis 11AD

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

Refs: 11875050; 11875049; 16384941; 20006823; 20238028; 20301475; 21791244Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IMPDH1 variants in ClinVar

10 Conditions Cataloged
not providedTotal: 623
not specifiedTotal: 132
IMPDH1-related disorderTotal: 81
Retinal dystrophyTotal: 60
Inborn genetic diseasesTotal: 58
Leber congenital amaurosis 11Total: 50
Retinitis pigmentosaTotal: 43
Retinitis pigmentosa 10Total: 29

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000883.4. 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.

EffectPLPVUSLBBSum
synonymous
11
clinvar
152
clinvar
2
clinvar
 165
missense
3
clinvar
24
clinvar
290
clinvar
22
clinvar
1
clinvar
 340
nonsense
5
clinvar
2
clinvar
2
clinvar
 9
start loss
1
clinvar
 1
frameshift
8
clinvar
2
clinvar
5
clinvar
 15
splice donor/acceptor (+/-2bp)
5
clinvar
4
clinvar
 9
Total16333131743539

Highest pathogenic variant AF is 0.000055444816

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000883.4RefSeqNP_000874.217MANE Select
ENST00000338791.11EnsemblENSP00000345096.617MANE Select
NM_001102605.2RefSeqNP_001096075.116Standard
NM_001142573.2RefSeqNP_001136045.114Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
impdh1aDanio rerio

Structure: iridophore

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Drug metabolism - other enzymes - Homo sapiens (human)
  • Purine metabolism - Homo sapiens (human)
  • Mycophenolic acid Pathway, Pharmacokinetics
  • Mycophenolic acid Pathway, Pharmacokinetics/Pharmacodynamics
  • Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics

Biological Process

  • GMP biosynthetic process
  • GTP biosynthetic process
  • purine ribonucleoside monophosphate biosynthetic process
  • neutrophil degranulation
  • lymphocyte proliferation

Molecular Function

  • nucleotide binding
  • nucleic acid binding
  • DNA binding
  • RNA binding
  • IMP dehydrogenase activity

Cellular Component

  • extracellular region
  • nucleus
  • cytoplasm
  • cytosol
  • secretory granule lumen

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000338791
Coding exons
17
Length
17976
Individuals with no LoFs
125698
Homozygous LoFs
0
Heterozygous LoFs
50
Defined
125748
p
0.000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.692613500.7450.00002273836
Missense (PolyPhen)64111.420.574431355
Synonymous-0.6731551451.070.00001011239
Loss of Function2.831431.00.4510.00000173350

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000110.00011rare
Finnish0.000750.00074rare
European (Non-Finnish)0.000180.00018rare
South Asian0.0000980.000098rare
Other0.000490.00049rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate- limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors.;
Disease
DISEASE: Retinitis pigmentosa 10 (RP10) [MIM:180105]: 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:11875049, ECO:0000269|PubMed:11875050, ECO:0000269|PubMed:16384941}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leber congenital amaurosis 11 (LCA11) [MIM:613837]: A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. {ECO:0000269|PubMed:16384941}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0985

Intolerance Scores

LoFtool
0.0617
RVIS EVS
-0.24
RVIS percentile EVS
36.17

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.0749

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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