GeneBe

CYP4V2

protein-coding

cytochrome P450 family 4 subfamily V member 2, the group of Cytochrome P450 family 4

Gene summary

This gene encodes a member of the cytochrome P450 hemethiolate protein superfamily which are involved in oxidizing various substrates in the metabolic pathway. It is implicated in the metabolism of fatty acid precursors into n-3 polyunsaturated fatty acids. Mutations in this gene result in Bietti crystalline corneoretinal dystrophy. [provided by RefSeq, Jul 2008]

MANE transcript

NM_207352.4

Inheritance

AR

ClinVar variants

P:104U:260B:105

Top phenotype

Bietti crystalline corneoretinal dystrophy

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr4:186,191,567-186,213,463

External References & Databases

Ensembl (ENSG00000145476)NCBI Gene (285440)OMIM (608614)HGNC:23198GenCCUniProt (Q6ZWL3)AlphaFoldClinVar (CYP4V2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~21.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bietti crystalline corneoretinal dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008865

Submitter: Illumina

Bietti crystalline corneoretinal dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008865

Submitter: ClinGen

CYP4V2 was first reported in relation to Bietti crystalline corneoretinal dystrophy (BCD) in 2004 (Li et al, PMID 15042513). Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessively inherited disorder characterized by the presence of multiple shimmering yellow-white deposits in the posterior pole of the retina in association with atrophy of the retinal pigment epithelium (RPE) and chorioretinal atrophy (Garcia-Garcia et al, 2019, PMID PMID: 31440027). Over 60 variants in CTP4V2 in patients with BCD have been reported (Ng et al, 2016, PMID 27228076; Garcia-Garvia et al, 2019, PMID PMID: 31440027). The mechanism of pathogenicity is loss of function. This curation includes six variants (nonsense, missense, small deletion) in 44 probands from 3 publications (Lin et al, 2005, PMID 15937078; Xie et al, 2020, PMID 33306817; Murakami et al, 2021, PMID 33636399). One of these variants curated, c.802-8_810delinsGC, is the most common variant in East Asian individuals with BCD. More evidence 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 RT-PCR data showing highest expression in retina (Li et al, 2004; PMID 150425130), functional studies of CYP4V2 variants (Nakano et al, 2012, PMID 22772592; Hata et al, 2018, PMID 29581279) and the features noted in a knockout mouse model (Lockhart et al, 2014, PMID 25118264). In summary, CYP4V2 is definitively associated with Bietti crystalline corneoretinal dystrophy, inherited in an autosomal recessive manner. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on April 1st, 2021.

Bietti crystalline corneoretinal dystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008865

Submitter: Labcorp Genetics (formerly Invitae)

Bietti crystalline corneoretinal dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008865

Submitter: G2P

Bietti crystalline corneoretinal dystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008865

Submitter: Orphanet

Bietti crystalline corneoretinal dystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008865

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Bietti crystalline corneoretinal dystrophyAR

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

Comments: Subclinical manifestations have been described in heterozygous individuals

Refs: 5299874; 306693; 3493804; 2783846; 11001583; 15042513; 18398705; 19508456; 21385027; 21565171; 22087103; 22497028; 22605929; 22693542; 22772592; 23143451; 23221965; 23242590; 23538635Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP4V2 variants in ClinVar

11 Conditions Cataloged
not providedTotal: 455
Bietti crystalline corneoretinal dystrophyTotal: 95
CYP4V2-related disorderTotal: 86
Inborn genetic diseasesTotal: 60
Retinal dystrophyTotal: 52
not specifiedTotal: 42
Corneal dystrophyTotal: 35
Retinitis pigmentosaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_207352.4. 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
3
clinvar
88
clinvar
2
clinvar
 93
missense
12
clinvar
22
clinvar
251
clinvar
14
clinvar
1
clinvar
 300
nonsense
12
clinvar
7
clinvar
1
clinvar
 20
start loss
1
clinvar
1
clinvar
 2
frameshift
17
clinvar
13
clinvar
 30
splice donor/acceptor (+/-2bp)
10
clinvar
10
clinvar
4
clinvar
 24
Total52522601023469

Highest pathogenic variant AF is 0.000110285146

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_207352.4RefSeqNP_997235.311MANE Select
ENST00000378802.5EnsemblENSP00000368079.411MANE Select
ENST00000905173.1EnsemblENSP00000575232.111Standard
ENST00000905173.2EnsemblENSP00000575232.111Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Oxidation by Cytochrome P450
  • Metapathway biotransformation Phase I and II
  • Signaling by GPCR
  • Signal Transduction
  • Phase I - Functionalization of compounds

Biological Process

  • retinoid metabolic process
  • visual perception
  • fatty acid omega-oxidation
  • sterol metabolic process
  • response to stimulus

Molecular Function

  • monooxygenase activity
  • iron ion binding
  • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
  • heme binding

Cellular Component

  • endoplasmic reticulum membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000378802
Coding exons
11
Length
21937
Individuals with no LoFs
125576
Homozygous LoFs
0
Heterozygous LoFs
172
Defined
125748
p
0.000684
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1213052991.020.00001663456
Missense (PolyPhen)112107.961.03741261
Synonymous0.919961080.8880.00000591966
Loss of Function1.421927.00.7050.00000129311

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000370.00037rare
Latino/Admixed American0.000610.00061rare
Ashkenazi Jewish00.0absent
East Asian0.000920.00092rare
Finnish0.00170.0017notable
European (Non-Finnish)0.000750.00075rare
South Asian0.0000650.000065rare
Other0.000660.00065rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Omega-hydroxylase that oxidizes medium-chain saturated fatty acids and polyunsaturated omega-3 fatty acids, and which plays a role in fatty acid and steroid metabolism in the eye (PubMed:19661213, PubMed:22772592). Catalyzes the omega- hydroxylation of medium-chain saturated fatty acids such as laurate, myristate and palmitate in an NADPH-dependent pathway. The substrate specificity is higher for myristate > laurate > palmitate (C14>C16>C12) (PubMed:19661213). Acts as a polyunsaturated omega-3 fatty acids hydroxylase by mediating oxidation of docosahexaenoate (DHA) to 22-hydroxydocosahexaenoate (PubMed:22772592). Also produces some 21-hydroxydocosahexaenoate. Also converts eicosapentaenoate (EPA) to 20- hydroxyeicosapentaenoate (20-OH-EPA) (PubMed:22772592). {ECO:0000269|PubMed:19661213, ECO:0000269|PubMed:22772592}.;

Recessive Scores

pRec
0.272

Intolerance Scores

LoFtool
0.535
RVIS EVS
0.42
RVIS percentile EVS
77.23

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.641

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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