CYB5R3
protein-codingcytochrome b5 reductase 3
Gene summary
This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]
- DIA1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~105.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009606
Submitter: ClinGen
*CYB5R3* was first reported in relation to autosomal recessive methemoglobinemia due to deficiency of methemoglobin reductase in 1990 (Kobayashi et al., PMID: 21047882). This disease entity contains two related conditions, methemoglobinemia type I and type II (MIM#250800), which are primarily differentiated by the severity of their clinical presentation (PMID: 18318771; 34467556). Methemoglobinemia type I is characterized by early onset primary cyanosis and elevated serum methemoglobin. Affected individuals have a normal life expectancy and are often asymptomatic. Methemoglobinemia type II is characterized by the same symptoms as type I, with additional neurological involvement which may include global developmental delay, intellectual disability, progressive microcephaly, and/or generalized hypertonia. Patients with methemoglobinemia type II typically do not survive to adulthood. Serum methemoglobin levels do not necessarily correlate with clinical presentation, nor do variant type or genomic position, complicating attempts at genotype-phenotype correlation. However, biallelic null/truncating variants are generally associated with methemoglobinemia type II, while missense variants may be associated with either presentation (PMID: 18318771). The mechanism of pathogenicity is known to be loss of function. Seven variants (missense, nonsense, canonical splice site, and splice region) that have been reported in five probands in five publications (PMIDs: 2107882; 7718898; 8874222; 10874300; 15744830) are included in this curation. More evidence representing a larger suite of variant types is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by expression studies, *in vitro* functional assays, physical interactions with other proteins associated with methemoglobinemia, and cell culture models (PMIDs: 18973815, 24450884, 26611738, 29111436, 36441026). In summary, there is definitive evidence supporting the relationship between *CYB5R3* and autosomal recessive methemoglobinemia due to deficiency of methemoglobin reductase. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time with no emergence of contradictory evidence. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on November 22, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0009606
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009606
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0001117
Submitter: Illumina
Inheritance Pattern: AR
Disease ID:MONDO:0018963
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Hematologic; Neurologic
Intervention: Biochemical; Pharmacogenomic
Rationale: Some forms of disease are responsive to medical therapy (eg, with ascorbic acid), though neurological manifestations in severe forms have not been described as being impacted by this type of management; In treatment with certain medications (eg, Dapsone), genotyping may assist in the prevention and/or early treatment of adverse reactions
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CYB5R3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000398.7. 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 | 41 | 2 | 45 | ||
| missense | 8 | 20 | 114 | 8 | 2 | 152 |
| nonsense | 7 | 1 | 8 | |||
| start loss | 2 | 2 | ||||
| frameshift | 2 | 1 | 1 | 4 | ||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 2 | 6 | ||
| Total | 18 | 25 | 121 | 49 | 4 | 217 |
Highest pathogenic variant AF is 0.00012083222
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000389.1 | 9 | MANE Select | |
| Ensembl | ENSP00000338461.6 | 9 | MANE Select | |
| RefSeq | NP_001123291.1 | 8 | Standard | |
| RefSeq | NP_001165131.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)
- Methylene Blue Pathway, Pharmacodynamics
- Oxidation by Cytochrome P450
- Neutrophil degranulation
- Phase I - Functionalization of compounds
Biological Process
- cholesterol biosynthetic process
- blood circulation
- L-ascorbic acid metabolic process
- neutrophil degranulation
- oxidation-reduction process
Molecular Function
- cytochrome-b5 reductase activity, acting on NAD(P)H
- protein binding
- AMP binding
- ADP binding
- NAD binding
Cellular Component
- extracellular region
- cytoplasm
- mitochondrion
- mitochondrial outer membrane
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361740
- Coding exons
- 9
- Length
- 31729
- Individuals with no LoFs
- 125715
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 33
- Defined
- 125748
- p
- 0.000131
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.419 | 222 | 205 | 1.08 | 0.0000136 | 2176 |
| Missense (PolyPhen) | 80 | 78.119 | 1.0241 | 862 | ||
| Synonymous | 0.119 | 80 | 81.4 | 0.983 | 0.00000547 | 639 |
| Loss of Function | 2.03 | 9 | 18.4 | 0.489 | 0.00000104 | 188 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.00051 | 0.00051 | rare |
| European (Non-Finnish) | 0.000088 | 0.000088 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction.;
- Disease
- DISEASE: Methemoglobinemia CYB5R3-related (METHB-CYB5R3) [MIM:250800]: A form of methemoglobinemia, a hematologic disease characterized by the presence of excessive amounts of methemoglobin in blood cells, resulting in decreased oxygen carrying capacity of the blood, cyanosis and hypoxia. There are two types of methemoglobinemia CYB5R3-related. In type 1, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type 2, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes and all body tissues. Type 2 methemoglobinemia is associated with mental deficiency and other neurologic symptoms. {ECO:0000269|PubMed:10807796, ECO:0000269|PubMed:12393396, ECO:0000269|PubMed:1400360, ECO:0000269|PubMed:15622768, ECO:0000269|PubMed:15953014, ECO:0000269|PubMed:1707593, ECO:0000269|PubMed:1898726, ECO:0000269|PubMed:7718898, ECO:0000269|PubMed:8119939, ECO:0000269|PubMed:9695975, ECO:0000269|PubMed:9886302}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.282
Intolerance Scores
- LoFtool
- 0.0159
- RVIS EVS
- 0.51
- RVIS percentile EVS
- 80.2
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.532
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |