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UniProtKB/Swiss-Prot P16435: Variant p.Arg454His

NADPH--cytochrome P450 reductase
Gene: POR
Chromosomal location: 7q11.2
Variant information

Variant position:  454
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Arginine (R) to Histidine (H) at position 454 (R454H, p.Arg454His).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from large size and basic (R) to medium size and polar (H)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in 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.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Involvement in 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.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In ABS1 and DISPORD; significant reduction of activity.
Any additional useful information about the variant.



Sequence information

Variant position:  454
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  677
The length of the canonical sequence.

Location on the sequence:   CPSLRPPIDHLCELLPRLQA  R YYSIASSSKVHPNSVHICAV
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         CPSLRPPIDHLCELLPRLQARYYSIASSSKVHPNSVHICAV

Mouse                         YPSLRPPIDHLCELLPRLQARYYSIASSSKVHPNSVHICAV

Rat                           YPSLRPPIDHLCELLPRLQARYYSIASSSKVHPNSVHICAV

Pig                           YPSLRPPIDHLCERLPRLQARYYSIASSSKVHPNSVHICAV

Bovine                        YPSLRPPIDHLCELLPRLQARYYSIASSSKVHPNSVHICAV

Rabbit                        YPSLRPPIDHLCELLPRLQARYYSIASSSKVHPNSVHICAV

Drosophila                    IKSCRPPIDHVCELLPRLQPRYYSISSSAKLHPTDVHVTAV

Slime mold                    FPGLQPLIAHFLEFTPRLPARMYSISSSPHNKNGVVSITSV

Baker's yeast                 AKWDTVPMQFLVESVPQMTPRYYSISSSSLSEKQTVHVTSI

Fission yeast                 APFTKLPFSMLLENMAHMKPRYYSISSSSVVHPDKVHVTAV

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 2 – 677 NADPH--cytochrome P450 reductase
Topological domain 43 – 677 Cytoplasmic
Domain 279 – 521 FAD-binding FR-type
Nucleotide binding 454 – 457 FAD
Beta strand 454 – 457


Literature citations

Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome.
Adachi M.; Tachibana K.; Asakura Y.; Yamamoto T.; Hanaki K.; Oka A.;
Am. J. Med. Genet. A 128:333-339(2004)
Cited for: VARIANT ABS1 HIS-454;

Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients.
Fukami M.; Horikawa R.; Nagai T.; Tanaka T.; Naiki Y.; Sato N.; Okuyama T.; Nakai H.; Soneda S.; Tachibana K.; Matsuo N.; Sato S.; Homma K.; Nishimura G.; Hasegawa T.; Ogata T.;
J. Clin. Endocrinol. Metab. 90:414-426(2005)
Cited for: VARIANTS ABS1 HIS-454; CYS-575 AND 608-LEU--TRP-617 DELINS ARG; VARIANT VAL-500;

Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.
Arlt W.; Walker E.A.; Draper N.; Ivison H.E.; Ride J.P.; Hammer F.; Chalder S.M.; Borucka-Mankiewicz M.; Hauffa B.P.; Malunowicz E.M.; Stewart P.M.; Shackleton C.H.L.;
Lancet 363:2128-2135(2004)
Cited for: VARIANTS DISPORD ASP-178; PRO-284; HIS-454 AND TYR-566; CHARACTERIZATION OF VARIANTS DISPORD ASP-178; PRO-284; HIS-454 AND TYR-566;

Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.
Flueck C.E.; Tajima T.; Pandey A.V.; Arlt W.; Okuhara K.; Verge C.F.; Jabs E.W.; Mendonca B.B.; Fujieda K.; Miller W.L.;
Nat. Genet. 36:228-230(2004)
Cited for: VARIANTS ABS1 PRO-284; HIS-454 AND GLU-489; VARIANTS DISPORD TYR-566 AND PHE-605; CHARACTERIZATION OF VARIANTS ABS1 PRO-284; HIS-454 AND GLU-489; CHARACTERIZATION OF VARIANTS DISPORD TYR-566 AND PHE-605;

Identical NR5A1 missense mutations in two unrelated 46,XX individuals with testicular tissues.
Igarashi M.; Takasawa K.; Hakoda A.; Kanno J.; Takada S.; Miyado M.; Baba T.; Morohashi K.I.; Tajima T.; Hata K.; Nakabayashi K.; Matsubara Y.; Sekido R.; Ogata T.; Kashimada K.; Fukami M.;
Hum. Mutat. 38:39-42(2017)
Cited for: VARIANT HIS-454;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.