POR

protein-coding

cytochrome p450 oxidoreductase, the group of Small nucleolar RNA protein coding host genes|MicroRNA protein coding host genes

Gene summary

This gene encodes an endoplasmic reticulum membrane oxidoreductase that is essential for multiple metabolic processes, including reactions catalyzed by cytochrome P450 proteins for metabolism of steroid hormones, drugs and xenobiotics. The encoded protein has a flavin adenine dinucleotide (FAD)-binding domain and a flavodoxin-like domain which bind two cofactors, FAD and FMN, that allow it to donate electrons directly from NADPH to all microsomal P450 enzymes. Mutations in this gene cause a complex set of disorders, including apparent combined P450C17 and P450C21 deficiency, amenorrhea and disordered steroidogenesis, congenital adrenal hyperplasia and Antley-Bixler syndrome, that resemble those caused by defects in steroid metabolizing enzymes such as aromatase, 21-hydroxylase, and 17 alpha-hydroxylase. [provided by RefSeq, Aug 2020]

MANE transcript

NM_001395413.1

Inheritance

ClinVar variants

P:110U:253B:304

Top phenotype

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis; Disordered steroidogenesis due to cytochrome P450 oxidoreductase deficiency

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr7:75,899,200-75,986,855

External References & Databases

Ensembl (ENSG00000127948)

Transcript & Mutation Effects

hg38 • Region Span ~87.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008726

Submitter: Ambry Genetics

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008726

Submitter: PanelApp Australia

congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013310

Submitter: Orphanet

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008726

Submitter: Ambry Genetics

congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013310

Submitter: Labcorp Genetics (formerly Invitae)

congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013310

Submitter: PanelApp Australia

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008726

Submitter: ClinGen

POR was first reported in relation to autosomal recessive POR-related Antley- Bixler Syndrome in 2004 (Flück et al., PMID: 14758361). Antley-Bixler Syndrome is a rare syndromic craniosynostosis characterized by midface hypoplasia, radiohumeral synostosis, femoral bowing, and joint contractures. Phenotypes specific to POR-related Antley-Bixler include steroidogenesis and genital anomalies. There is variation seen in the literature, with some cases with pathogenic POR variants having isolated craniofacial phenotypes or isolated genital anomalies and steroidogenesis. The cases included in this curation for POR and POR-related Antley-Bixler Syndrome exhibited both craniofacial phenotypes and genital anomalies/steroidogenesis. This curation includes 6 variants (missense, splice, nonsense, frameshift) have been reported in 7 probands from 6 publications (PMIDs: 32615689, 18853185, 32851239, 20124576, 26670660, 28841001). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease association is also supported by animal models and in vitro functional assays (PMIDs: 24086598, 15793702). In summary, POR is definitively associated with autosomal recessive POR-related Antley-Bixler Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Gene Clinical Validity Standard Operating Procedures (SOP) – Version 8.

Clinical Genomic Database (CGD)

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis; Disordered steroidogenesis due to cytochrome P450 oxidoreductase deficiencyAR

Manifestation: Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: Hydrocortisone replacement therapy can be effective for cortisol deficiency, including administation of stress-dose steroids; In males, testosterone therapy can help with undervirilization in puberty

Refs: 2932643; 0633130; 12116245; 11742006; 12917333; 15220035; 14758361; 14513299; 15793702; 16906539; 18559916; 19837910; 19884324; 20124576; 20410220; 20818252; 20844025; 21070833; 22162478

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POR variants in ClinVar

15 Conditions Cataloged

Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiencyTotal: 765

not providedTotal: 166

not specifiedTotal: 91

POR-related disorderTotal: 72

Inborn genetic diseasesTotal: 71

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesisTotal: 61

Antley-Bixler syndrome without genital anomalies or disordered steroidogenesisTotal: 12

Congenital adrenal hyperplasiaTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001395413.1. 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			4 clinvar	286 clinvar	2 clinvar	292
missense	7 clinvar	13 clinvar	240 clinvar	15 clinvar		275
nonsense	12 clinvar	8 clinvar				20
start loss						0
frameshift	32 clinvar	18 clinvar	1 clinvar			51
splice donor/acceptor (+/-2bp)	4 clinvar	16 clinvar	8 clinvar	1 clinvar		29
Total	55	55	253	302	2	667

Highest pathogenic variant AF is 0.00031186294

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 94 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001395413.1	RefSeq	NP_001382342.1	15	MANE Select
ENST00000461988.6	Ensembl	ENSP00000419970.2	15	MANE Select
NM_001367562.3	RefSeq	NP_001354491.2	15	Standard
NM_001382655.3	RefSeq	NP_001369584.2	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Doxorubicin Pathway, Pharmacokinetics
Zidovudine Pathway, Pharmacokinetics/Pharmacodynamics
Doxorubicin Metabolism Pathway
Integrated Lung Cancer Pathway
Oxidation by Cytochrome P450

Biological Process

regulation of growth plate cartilage chondrocyte proliferation
xenobiotic metabolic process
response to nutrient
carnitine metabolic process
response to hormone

Molecular Function

NADPH-hemoprotein reductase activity
cytochrome-b5 reductase activity, acting on NAD(P)H
protein binding
nitric oxide dioxygenase activity
electron transfer activity

Cellular Component

mitochondrion
endoplasmic reticulum membrane
cytosol
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000461988
Coding exons: 15
Length: 87656
Individuals with no LoFs: 124568
Homozygous LoFs: 0
Heterozygous LoFs: 92
Defined: 124660
p: 0.000369

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0717	448	444	1.01	0.0000306	4384
Missense (PolyPhen)		125	141.01	0.88647		1301
Synonymous	-0.668	214	202	1.06	0.0000162	1303
Loss of Function	2.31	21	35.9	0.585	0.00000187	381

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00030	0.00026	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.00013	0.000093	rare
European (Non-Finnish)	0.00050	0.00048	rare
South Asian	0.00044	0.00042	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5. {ECO:0000255|HAMAP- Rule:MF_03212}.;
Disease: DISEASE: Antley-Bixler syndrome, with genital anomalies and disordered steroidogenesis (ABS1) [MIM:201750]: A disease characterized by the association of Antley-Bixler syndrome with steroidogenesis defects and abnormal genitalia. Antley-Bixler syndrome is characterized by craniosynostosis, radiohumeral synostosis present from the perinatal period, midface hypoplasia, choanal stenosis or atresia, femoral bowing and multiple joint contractures. {ECO:0000269|PubMed:14758361, ECO:0000269|PubMed:15264278, ECO:0000269|PubMed:15483095}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Disordered steroidogenesis due to cytochrome P450 oxidoreductase deficiency (DISPORD) [MIM:613571]: A disorder resulting in a rare variant of congenital adrenal hyperplasia, with apparent combined P450C17 and P450C21 deficiency and accumulation of steroid metabolites. Affected girls are born with ambiguous genitalia, but their circulating androgens are low and virilization does not progress. Conversely, affected boys are sometimes born undermasculinized. Boys and girls can present with bone malformations, in some cases resembling the pattern seen in patients with Antley-Bixler syndrome. {ECO:0000269|PubMed:14758361, ECO:0000269|PubMed:15220035}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.542

Intolerance Scores

LoFtool: 0.329
RVIS EVS: -1.52
RVIS percentile EVS: 3.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.986