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UniProtKB/Swiss-Prot P08686: Variant p.Val281Leu

Steroid 21-hydroxylase
Gene: CYP21A2
Variant information

Variant position:  281
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 Valine (V) to Leucine (L) at position 281 (V281L, p.Val281Leu).
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:  Similar physico-chemical property. Both residues are medium size and hydrophobic.
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  1
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:  Adrenal hyperplasia 3 (AH3) [MIM:201910]: A form of congenital adrenal hyperplasia, a common recessive disease due to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature. Four clinical types: 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, less severely affected patients), with normal aldosterone biosynthesis, 'non-classic form' or late-onset (NC or LOAH) and 'cryptic' (asymptomatic). {ECO:0000269|PubMed:10051010, ECO:0000269|PubMed:10094562, ECO:0000269|PubMed:10198222, ECO:0000269|PubMed:10364682, ECO:0000269|PubMed:10391209, ECO:0000269|PubMed:10408778, ECO:0000269|PubMed:10408786, ECO:0000269|PubMed:10443693, ECO:0000269|PubMed:10496074, ECO:0000269|PubMed:10720040, ECO:0000269|PubMed:11232002, ECO:0000269|PubMed:11598371, ECO:0000269|PubMed:11600539, ECO:0000269|PubMed:11746135, ECO:0000269|PubMed:12213891, ECO:0000269|PubMed:12222711, ECO:0000269|PubMed:12788866, ECO:0000269|PubMed:12887291, ECO:0000269|PubMed:12915679, ECO:0000269|PubMed:1406699, ECO:0000269|PubMed:1406709, ECO:0000269|PubMed:14676460, ECO:0000269|PubMed:14715874, ECO:0000269|PubMed:1496017, ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:15126570, ECO:0000269|PubMed:16046588, ECO:0000269|PubMed:1644925, ECO:0000269|PubMed:16984992, ECO:0000269|PubMed:18319307, ECO:0000269|PubMed:18381579, ECO:0000269|PubMed:18445671, ECO:0000269|PubMed:1864962, ECO:0000269|PubMed:1937474, ECO:0000269|PubMed:20080860, ECO:0000269|PubMed:2072928, ECO:0000269|PubMed:21169732, ECO:0000269|PubMed:22014889, ECO:0000269|PubMed:2303461, ECO:0000269|PubMed:27721825, ECO:0000269|PubMed:3038528, ECO:0000269|PubMed:3257825, ECO:0000269|PubMed:3260007, ECO:0000269|PubMed:3267225, ECO:0000269|PubMed:3497399, ECO:0000269|PubMed:3871526, ECO:0000269|PubMed:7749410, ECO:0000269|PubMed:8478006, ECO:0000269|PubMed:8485582, ECO:0000269|PubMed:8989258, ECO:0000269|PubMed:9067760, ECO:0000269|PubMed:9187661, ECO:0000269|PubMed:9497336, ECO:0000269|PubMed:9580109}. 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 AH3; non-classic form; 50% activity; most common variant; normal KM but 20% reduced Vmax.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  281
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  494
The length of the canonical sequence.

Location on the sequence:   LQGVAQPSMEEGSGQLLEGH  V HMAAVDLLIGGTETTANTLS
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                         LQGVAQPSMEEGSGQLLEGHVHMAAVDLLIGGTETTANTLS

                              LQRVGRLRAEEGCGQLLEGHVHMSVVDLFIGGTETTATTLS

Mouse                         LQGVEKQRDGKDEERLHEGHVHMSVVDLFIGGTETTATTLS

Rat                           LQGVEKQRDARDPGQLHERHVHMSVVDLFVGGTETTAATLS

Pig                           LQEAGRQRVEEGQGQLLEGHVHMSVVDLFIGGTETTANTLS

Bovine                        LQGVGRQRVEEGPGQLLEGHVHMSVVDLFIGGTETTASTLS

Cat                           LQGMGKPKVEKGHGRLLEGHVHMSVVDLFIGGTETTATTLS

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 1 – 494 Steroid 21-hydroxylase
Mutagenesis 268 – 268 S -> CMT. No loss of function.
Mutagenesis 281 – 281 V -> I. Normal KM but 50% reduced Vmax.
Mutagenesis 281 – 281 V -> T. Normal KM but 10% reduced Vmax.
Helix 278 – 309


Literature citations

Nonsense mutation causing steroid 21-hydroxylase deficiency.
Globerman H.; Amor M.; Parker K.L.; New M.I.; White P.C.;
J. Clin. Invest. 82:139-144(1988)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANT AH3 LEU-281; VARIANT LEU-9 INS;

P450XXI (steroid 21-hydroxylase) gene deletions are not found in family studies of congenital adrenal hyperplasia.
Matteson K.J.; Phillips J.A. III; Miller W.L.; Chung B.C.; Orlando P.J.; Frisch H.; Ferrandez A.; Burr I.M.;
Proc. Natl. Acad. Sci. U.S.A. 84:5858-5862(1987)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 265-494 (ISOFORM 1); VARIANT AH3 LEU-281;

Mutations of P450c21 (steroid 21-hydroxylase) at Cys428, Val281, and Ser268 result in complete, partial, or no loss of enzymatic activity, respectively.
Wu D.-A.; Chung B.-C.;
J. Clin. Invest. 88:519-523(1991)
Cited for: CHARACTERIZATION OF VARIANT AH3 LEU-281; MUTAGENESIS OF SER-268 AND CYS-428;

Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14,DR1.
Speiser P.W.; New M.I.; White P.C.;
N. Engl. J. Med. 319:19-23(1988)
Cited for: VARIANTS AH3 LEU-211 AND LEU-281;

Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Speiser P.W.; Dupont J.; Zhu D.; Serrat J.; Buegeleisen M.; Tusie-Luna M.-T.; Lesser M.; New M.I.; White P.C.;
J. Clin. Invest. 90:584-595(1992)
Cited for: VARIANTS AH3 LEU-30; ASN-172; ASN-236; GLU-237; LYS-239; LEU-281 AND TRP-356;

Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency.
Barbat B.; Bogyo A.; Raux-Demay M.-C.; Kuttenn F.; Boue J.; Simon-Bouy B.; Serre J.-L.; Boue A.; Mornet E.;
Hum. Mutat. 5:126-130(1995)
Cited for: VARIANTS AH3 ASN-172; ASN-236; LEU-281 AND PRO-483; VARIANT SER-493;

Mutation analysis in patients with congenital adrenal hyperplasia in the Spanish population: identification of putative novel steroid 21-hydroxylase deficiency alleles associated with the classic form of the disease.
Lobato M.N.; Ordonez-Sanchez M.L.; Tusie-Luna M.T.; Meseguer A.;
Hum. Hered. 49:169-175(1999)
Cited for: VARIANTS AH3 LEU-30; VAL-90; ASN-172; ALA-178; LEU-281; CYS-291; HIS-354; TRP-356 AND SER-453;

Identification of CYP21 mutations, one novel, by single strand conformational polymorphism (SSCP) analysis.
Witchel S.F.; Smith R.; Suda-Hartman M.;
Hum. Mutat. 13:172-172(1999)
Cited for: VARIANTS AH3 TYR-169; LEU-281 AND GLN-356;

Steroid 21-hydroxylase deficiency: mutational spectrum in Denmark, three novel mutations, and in vitro expression analysis.
Ohlsson G.; Mueller J.; Skakkebaek N.E.; Schwartz M.;
Hum. Mutat. 13:482-486(1999)
Cited for: VARIANTS AH3 LEU-30; GLU-64; ASN-172; ASN-236; LEU-281; SER-291; TRP-356 AND VAL-362;

A rapid screening for steroid 21-hydroxylase mutations in patients with congenital adrenal hyperplasia.
Kapelari K.; Ghanaati Z.; Wollmann H.; Ventz M.; Ranke M.B.; Kofler R.; Peters H.;
Hum. Mutat. 13:505-505(1999)
Cited for: VARIANTS AH3 LEU-30; ASN-172; ASN-236; GLU-237; LYS-239; LEU-281 AND TRP-356;

A novel missense mutation, GLY424SER, in Brazilian patients with 21-hydroxylase deficiency.
Billerbeck A.E.C.; Bachega T.A.S.S.; Frazatto E.T.; Nishi M.Y.; Goldberg A.C.; Marin M.L.C.; Madureira G.; Monte O.; Arnhold I.J.P.; Mendonca B.B.;
J. Clin. Endocrinol. Metab. 84:2870-2872(1999)
Cited for: VARIANTS AH3 LEU-281; TRP-356 AND SER-424;

Molecular analysis of Japanese patients with steroid 21-hydroxylase deficiency.
Asanuma A.; Ohura T.; Ogawa E.; Sato S.; Igarashi Y.; Matsubara Y.; Iinuma K.;
J. Hum. Genet. 44:312-317(1999)
Cited for: VARIANTS AH3 LEU-30; ASN-172; LEU-281; TRP-356 AND SER-493; VARIANT THR-268;

Characterization of single-nucleotide polymorphisms in coding regions of human genes.
Cargill M.; Altshuler D.; Ireland J.; Sklar P.; Ardlie K.; Patil N.; Shaw N.; Lane C.R.; Lim E.P.; Kalyanaraman N.; Nemesh J.; Ziaugra L.; Friedland L.; Rolfe A.; Warrington J.; Lipshutz R.; Daley G.Q.; Lander E.S.;
Nat. Genet. 22:231-238(1999)
Cited for: VARIANTS AH3 LEU-281 AND SER-453; VARIANTS THR-268 AND SER-493;

Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany.
Krone N.; Braun A.; Roscher A.A.; Knorr D.; Schwarz H.P.;
J. Clin. Endocrinol. Metab. 85:1059-1065(2000)
Cited for: VARIANTS AH3 LEU-30; ASN-172; LEU-281; GLY-281; PHE-300; CYS-354; TRP-356 AND SER-453;

Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Deneux C.; Tardy V.; Dib A.; Mornet E.; Billaud L.; Charron D.; Morel Y.; Kuttenn F.;
J. Clin. Endocrinol. Metab. 86:207-213(2001)
Cited for: VARIANTS AH3 LEU-30; ASN-172; LEU-281; MET-317; TRP-356; CYS-435 AND SER-453;

Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation.
Baumgartner-Parzer S.M.; Schulze E.; Waldhaeusl W.; Pauschenwein S.; Rondot S.; Nowotny P.; Meyer K.; Frisch H.; Waldhauser F.; Vierhapper H.;
J. Clin. Endocrinol. Metab. 86:4771-4775(2001)
Cited for: VARIANTS AH3 LEU-30; ASN-172; LEU-281; SER-291; TRP-356; SER-424; HIS-426; SER-453 AND PRO-483; CHARACTERIZATION OF VARIANT AH3 HIS-426;

Non-classical 21-hydroxylase deficiency in children: association of adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone with the risk of compound heterozygosity with severe mutations.
Ezquieta B.; Cueva E.; Varela J.; Oliver A.; Fernandez J.; Jariego C.;
Acta Paediatr. 91:892-898(2002)
Cited for: VARIANTS AH3 LEU-30; ASN-172; LEU-281; LEU-283; TRP-356 AND SER-453;

Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease.
Dolzan V.; Stopar-Obreza M.; Zerjav-Tansek M.; Breskvar K.; Krzisnik C.; Battelino T.;
Eur. J. Endocrinol. 149:137-144(2003)
Cited for: VARIANTS AH3 THR-15; LEU-30; ASN-172; LEU-281 AND SER-453;

Follow-up of 68 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: relevance of genotype for management.
Pinto G.; Tardy V.; Trivin C.; Thalassinos C.; Lortat-Jacob S.; Nihoul-Fekete C.; Morel Y.; Brauner R.;
J. Clin. Endocrinol. Metab. 88:2624-2633(2003)
Cited for: VARIANTS AH3 LEU-30; LEU-62; ASN-172; LEU-281; PRO-341; TRP-356; SER-453 AND PRO-483;

CYP21 gene mutation analysis in 198 patients with 21-hydroxylase deficiency in The Netherlands: six novel mutations and a specific cluster of four mutations.
Stikkelbroeck N.M.; Hoefsloot L.H.; de Wijs I.J.; Otten B.J.; Hermus A.R.; Sistermans E.A.;
J. Clin. Endocrinol. Metab. 88:3852-3859(2003)
Cited for: VARIANTS AH3 ASN-172; LEU-281; ARG-291; TYR-301; PRO-341; TRP-356 AND GLN-483;

Functional analysis of two recurrent amino acid substitutions in the CYP21 gene from Italian patients with congenital adrenal hyperplasia.
Barbaro M.; Lajic S.; Baldazzi L.; Balsamo A.; Pirazzoli P.; Cicognani A.; Wedell A.; Cacciari E.;
J. Clin. Endocrinol. Metab. 89:2402-2407(2004)
Cited for: VARIANTS AH3 THR-15; LEU-30; LEU-281 AND SER-482; CHARACTERIZATION OF VARIANTS AH3 THR-15 AND SER-482;

Detection and assignment of CYP21 mutations using peptide mass signature genotyping.
Zeng X.; Witchel S.F.; Dobrowolski S.F.; Moulder P.V.; Jarvik J.W.; Telmer C.A.;
Mol. Genet. Metab. 82:38-47(2004)
Cited for: VARIANTS AH3 LEU-30; ASN-172; ASN-236; GLU-237; LYS-239; LEU-281; SER-291; GLN-356; TRP-356; TYR-365; SER-453; LEU-479 AND PRO-483; VARIANT ARG-102;

Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier.
Tardy V.; Menassa R.; Sulmont V.; Lienhardt-Roussie A.; Lecointre C.; Brauner R.; David M.; Morel Y.;
J. Clin. Endocrinol. Metab. 95:1288-1300(2010)
Cited for: VARIANTS AH3 THR-77; PRO-167; ASN-172; THR-230; LYS-233; LEU-281; SER-291; ASP-292; LYS-320; PRO-341; HIS-354; TRP-356; TRP-369; CYS-408; SER-424; HIS-426 AND SER-453; CHARACTERIZATION OF VARIANTS AH3 PRO-167; ASN-172; LEU-281; ASP-292; LYS-320; TRP-369 AND SER-424;

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.