UniProtKB/Swiss-Prot P10635: Variant p.Arg296Cys

Cytochrome P450 2D6
Gene: CYP2D6
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Variant information Variant position:

296 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

LB/B The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Arginine (R) to Cysteine (C) at position 296 (R296C, p.Arg296Cys). 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 (C) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score:

-3 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
Polymorphism:

Genetic variations in CYP2D6 are the cause of poor drug metabolism CYP2D6-related [MIM:608902]. The CYP2D6 gene is highly polymorphic. CYP2D6 activity ranges widely within a population comprising ultrarapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizer phenotypes. UM and PM are those most at risk for treatment failure or dose-dependent drug toxicity, respectively. Of the Caucasian populations of Europe and North America, 5%-10% are of the PM phenotype and are unable to metabolize the antihypersensitive drug debrisoquine and numerous other drugs. Different alleles are known, including CYP2D6*1 (PubMed:15768052), CYP2D6*2 (PubMed:25469868), CYP2D6*6B/6C (PubMed:7868129), CYP2D6*7 also known CYP2D6E (PubMed:7845481), CYP2D6*9 also known CYP2D6C (PubMed:1844820), CYP2D6*10 also known CYP2D6J (PubMed:8287064, PubMed:25469868), CYP2D6*12 (PubMed:8655150), CYP2D6*14 (PubMed:10064570), CYP2D6*17 also known CYP2D6Z (PubMed:8971426), CYP2D6*41B (PubMed:15768052), CYP2D6*45A (PubMed:15768052), CYP2D6*45B (PubMed:15768052), CYP2D6*46 (PubMed:15768052), CYP2D6*87 (PubMed:25469868), CYP2D6*88 (PubMed:25469868), CYP2D6*89 (PubMed:25469868), CYP2D6*90 (PubMed:25469868), CYP2D6*91 (PubMed:25469868), CYP2D6*93 (PubMed:25469868), C CYP2D6*94 (PubMed:25469868), CYP2D6*97 (PubMed:25469868) and CYP2D6*98 (PubMed:25469868). Isozymes CYP2D6.45 (Lys-155, Cys-296 and Thr-486) and CYP2D6.46 (His-26, Lys-155, Cys-296 and Thr-486) are functional (PubMed:15768052). The sequence shown is that of isozyme CYP2D6.1 corresponding to allele CYP2D6*1. Additional information on the polymorphism described.
Variant description:

In allele CYP2D6*2, allele CYP2D6*12, allele CYP2D6*14, allele CYP2D6*17, allele CYP2D6*45A, allele CYP2D6*45B and allele CYP2D6*46; significantly reduced monooxygenase activity toward anandamide; slight decrease of monooxygenase activity towards bufuralol. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs16947 [ dbSNP | Ensembl ]

Sequence information Variant position:

296 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

497 The length of the canonical sequence.
Location on the sequence:

LAEMEKAKGNPESSFNDENL R IVVADLFSAGMVTTSTTLAW 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                         LAEMEKAKGNPESSFNDENLRIVVADLFSAGMVTTSTTLAW

Chimpanzee                    LAEMEKAKGNPESSFNDENLRIVVADLFSAGIVTTSTTLAW

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.

Type	Positions	Description
Chain	1 – 497	Cytochrome P450 2D6
Binding site	301 – 301
Helix	292 – 323

Literature citations
Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans.
Gaedigk A.; Bhathena A.; Ndjountche L.; Pearce R.E.; Abdel-Rahman S.M.; Alander S.W.; Bradford L.D.; Rogan P.K.; Leeder J.S.;
Pharmacogenomics J. 5:173-182(2005)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE CYP2D6*1); IDENTIFICATION OF ALLELES CYP2D6*41B; CYP2D6*45A; CYP2D6*45B AND CYP2D6*46; VARIANTS HIS-26; LYS-155; CYS-296 AND THR-486; CHARACTERIZATION OF ISOZYMES CYP2D6.45 AND CYP2D6.46; The DNA sequence of human chromosome 22.
Dunham I.; Hunt A.R.; Collins J.E.; Bruskiewich R.; Beare D.M.; Clamp M.; Smink L.J.; Ainscough R.; Almeida J.P.; Babbage A.K.; Bagguley C.; Bailey J.; Barlow K.F.; Bates K.N.; Beasley O.P.; Bird C.P.; Blakey S.E.; Bridgeman A.M.; Buck D.; Burgess J.; Burrill W.D.; Burton J.; Carder C.; Carter N.P.; Chen Y.; Clark G.; Clegg S.M.; Cobley V.E.; Cole C.G.; Collier R.E.; Connor R.; Conroy D.; Corby N.R.; Coville G.J.; Cox A.V.; Davis J.; Dawson E.; Dhami P.D.; Dockree C.; Dodsworth S.J.; Durbin R.M.; Ellington A.G.; Evans K.L.; Fey J.M.; Fleming K.; French L.; Garner A.A.; Gilbert J.G.R.; Goward M.E.; Grafham D.V.; Griffiths M.N.D.; Hall C.; Hall R.E.; Hall-Tamlyn G.; Heathcott R.W.; Ho S.; Holmes S.; Hunt S.E.; Jones M.C.; Kershaw J.; Kimberley A.M.; King A.; Laird G.K.; Langford C.F.; Leversha M.A.; Lloyd C.; Lloyd D.M.; Martyn I.D.; Mashreghi-Mohammadi M.; Matthews L.H.; Mccann O.T.; Mcclay J.; Mclaren S.; McMurray A.A.; Milne S.A.; Mortimore B.J.; Odell C.N.; Pavitt R.; Pearce A.V.; Pearson D.; Phillimore B.J.C.T.; Phillips S.H.; Plumb R.W.; Ramsay H.; Ramsey Y.; Rogers L.; Ross M.T.; Scott C.E.; Sehra H.K.; Skuce C.D.; Smalley S.; Smith M.L.; Soderlund C.; Spragon L.; Steward C.A.; Sulston J.E.; Swann R.M.; Vaudin M.; Wall M.; Wallis J.M.; Whiteley M.N.; Willey D.L.; Williams L.; Williams S.A.; Williamson H.; Wilmer T.E.; Wilming L.; Wright C.L.; Hubbard T.; Bentley D.R.; Beck S.; Rogers J.; Shimizu N.; Minoshima S.; Kawasaki K.; Sasaki T.; Asakawa S.; Kudoh J.; Shintani A.; Shibuya K.; Yoshizaki Y.; Aoki N.; Mitsuyama S.; Roe B.A.; Chen F.; Chu L.; Crabtree J.; Deschamps S.; Do A.; Do T.; Dorman A.; Fang F.; Fu Y.; Hu P.; Hua A.; Kenton S.; Lai H.; Lao H.I.; Lewis J.; Lewis S.; Lin S.-P.; Loh P.; Malaj E.; Nguyen T.; Pan H.; Phan S.; Qi S.; Qian Y.; Ray L.; Ren Q.; Shaull S.; Sloan D.; Song L.; Wang Q.; Wang Y.; Wang Z.; White J.; Willingham D.; Wu H.; Yao Z.; Zhan M.; Zhang G.; Chissoe S.; Murray J.; Miller N.; Minx P.; Fulton R.; Johnson D.; Bemis G.; Bentley D.; Bradshaw H.; Bourne S.; Cordes M.; Du Z.; Fulton L.; Goela D.; Graves T.; Hawkins J.; Hinds K.; Kemp K.; Latreille P.; Layman D.; Ozersky P.; Rohlfing T.; Scheet P.; Walker C.; Wamsley A.; Wohldmann P.; Pepin K.; Nelson J.; Korf I.; Bedell J.A.; Hillier L.W.; Mardis E.; Waterston R.; Wilson R.; Emanuel B.S.; Shaikh T.; Kurahashi H.; Saitta S.; Budarf M.L.; McDermid H.E.; Johnson A.; Wong A.C.C.; Morrow B.E.; Edelmann L.; Kim U.J.; Shizuya H.; Simon M.I.; Dumanski J.P.; Peyrard M.; Kedra D.; Seroussi E.; Fransson I.; Tapia I.; Bruder C.E.; O'Brien K.P.; Wilkinson P.; Bodenteich A.; Hartman K.; Hu X.; Khan A.S.; Lane L.; Tilahun Y.; Wright H.;
Nature 402:489-495(1999)
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]; VARIANTS CYS-296 AND THR-486; The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
The MGC Project Team;
Genome Res. 14:2121-2127(2004)
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2); VARIANTS CYS-296 AND THR-486; Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6.
Sridar C.; Snider N.T.; Hollenberg P.F.;
Drug Metab. Dispos. 39:782-788(2011)
Cited for: FUNCTION; CATALYTIC ACTIVITY; CHARACTERIZATION OF VARIANT CYS-296; Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population.
Solus J.F.; Arietta B.J.; Harris J.R.; Sexton D.P.; Steward J.Q.; McMunn C.; Ihrie P.; Mehall J.M.; Edwards T.L.; Dawson E.P.;
Pharmacogenomics 5:895-931(2004)
Cited for: VARIANTS MET-11; HIS-26; SER-34; MET-91; ARG-94; ILE-107; ILE-120; LYS-155; SER-237; CYS-296; LYS-418; ALA-469; TYR-478 AND THR-486; In vitro functional assessment of 22 newly identified CYP2D6 allelic variants in the Chinese population.
Dai D.P.; Geng P.W.; Wang S.H.; Cai J.; Hu L.M.; Nie J.J.; Hu J.H.; Hu G.X.; Cai J.P.;
Basic Clin. Pharmacol. Toxicol. 117:39-43(2015)
Cited for: VARIANTS VAL-5; GLN-25; SER-34; ALA-104; SER-142; ARG-147; SER-161; LEU-164; LYS-215; SER-219; PRO-249; CYS-296; MET-327; ASN-336; GLY-337; MET-342; GLN-344; CYS-440; LEU-457; ASP-463; THR-486 AND CYS-497;

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.