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UniProtKB/Swiss-Prot Q30201: Variant p.Cys282Tyr

Hereditary hemochromatosis protein
Gene: HFE
Variant information

Variant position:  282
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 Cysteine (C) to Tyrosine (Y) at position 282 (C282Y, p.Cys282Tyr).
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 medium size and polar (C) to large size and aromatic (Y)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
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:  Hemochromatosis 1 (HFE1) [MIM:235200]: A disorder of iron metabolism characterized by iron overload. Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. {ECO:0000269|PubMed:10094552, ECO:0000269|PubMed:10194428, ECO:0000269|PubMed:10401000, ECO:0000269|PubMed:10575540, ECO:0000269|PubMed:11423500, ECO:0000269|PubMed:11446670, ECO:0000269|PubMed:12542741, ECO:0000269|PubMed:12584229, ECO:0000269|PubMed:12737937, ECO:0000269|PubMed:14633868, ECO:0000269|PubMed:15046077, ECO:0000269|PubMed:15965644, ECO:0000269|PubMed:18157833, ECO:0000269|PubMed:8696333, ECO:0000269|PubMed:9024376, ECO:0000269|PubMed:9106528, ECO:0000269|PubMed:9620340, ECO:0000269|Ref.25}. 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 HFE1; associated with susceptibility to porphyria cutanea tarda; associated with increased serum transferrin levels; higher frequency in patients with type 2 diabetes than in controls.
Any additional useful information about the variant.

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



Sequence information

Variant position:  282
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  348
The length of the canonical sequence.

Location on the sequence:   GTYQGWITLAVPPGEEQRYT  C QVEHPGLDQPLIVIWEPSPS
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                         GTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWEPSPS

Chimpanzee                    GTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWEPSPS

Mouse                         ETYQGWLTLAVAPGDETRFTCQVEHPGLDQPLTASWEPLQS

Rat                           GTYQGWLTLAVAPGEETRFSCQVEHPGLDQPLTATWEPSRS

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 23 – 348 Hereditary hemochromatosis protein
Topological domain 23 – 306 Extracellular
Domain 207 – 298 Ig-like C1-type
Region 206 – 297 Alpha-3
Disulfide bond 225 – 282
Alternative sequence 27 – 298 Missing. In isoform 11.
Alternative sequence 162 – 348 Missing. In isoform 9.
Alternative sequence 277 – 348 Missing. In isoform 8.
Beta strand 280 – 285


Literature citations

A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.
Feder J.N.; Gnirke A.; Thomas W.; Tsuchihashi Z.; Ruddy D.A.; Basava A.; Dormishian F.; Domingo R. Jr.; Ellis M.C. Jr.; Fullan A.; Hinton L.M.; Jones N.L.; Kimmel B.E.; Kronmal G.S.; Lauer P.; Lee V.K.; Loeb D.B.; Mapa F.A.; McClelland E.; Meyer N.C.; Mintier G.A.; Moeller N.; Moore T.; Morikang E.; Prass C.E.; Quintana L.; Starnes S.M.; Schatzman R.C.; Brunke K.J.; Drayna D.T.; Risch N.J.; Bacon B.R.; Wolff R.K.;
Nat. Genet. 13:399-409(1996)
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1); VARIANT HFE1 TYR-282; VARIANT ASP-63;

Submission
NIEHS SNPs program;
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS MET-53; ASP-63; GLN-224 AND TYR-282;

Mutation analysis of the HLA-H gene in Italian hemochromatosis patients.
Carella M.; D'Ambrosio L.; Totaro A.; Grifa A.; Valentino M.A.; Piperno A.; Girelli D.; Roetto A.; Franco B.; Gasparini P.; Camaschella C.;
Am. J. Hum. Genet. 60:828-832(1997)
Cited for: VARIANT HFE1 TYR-282; VARIANT ASP-63;

Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda.
Roberts A.G.; Whatley S.D.; Morgan R.R.; Worwood M.; Elder G.H.;
Lancet 349:321-323(1997)
Cited for: VARIANT HFE1 TYR-282; ASSOCIATION WITH PORPHYRIA CUTANEA TARDA;

Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America.
Bonkovsky H.L.; Poh-Fitzpatrick M.; Pimstone N.; Obando J.; Di Bisceglie A.; Tattrie C.; Tortorelli K.; LeClair P.; Mercurio M.G.; Lambrecht R.W.;
Hepatology 27:1661-1669(1998)
Cited for: VARIANT HFE1 TYR-282; VARIANT ASP-63;

HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis.
Mura C.; Raguenes O.; Ferec C.;
Blood 93:2502-2505(1999)
Cited for: VARIANTS HFE1 CYS-65 AND TYR-282; VARIANT ASP-63;

A retrospective anonymous pilot study in screening newborns for HFE mutations in Scandinavian populations.
Merryweather-Clarke A.T.; Simonsen H.; Shearman J.D.; Pointon J.J.; Norgaard-Pedersen B.; Robson K.J.H.;
Hum. Mutat. 13:154-159(1999)
Cited for: VARIANT HFE1 TYR-282; VARIANT ASP-63;

Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda.
Brady J.J.; Jackson H.A.; Roberts A.G.; Morgan R.R.; Whatley S.D.; Rowlands G.L.; Darby C.; Shudell E.; Watson R.; Paiker J.; Worwood M.W.; Elder G.H.;
J. Invest. Dermatol. 115:868-874(2000)
Cited for: VARIANTS ASP-63 AND TYR-282;

Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy.
Moczulski D.K.; Grzeszczak W.; Gawlik B.;
Diabetes Care 24:1187-1191(2001)
Cited for: VARIANT HFE1 TYR-282; VARIANT ASP-63; ASSOCIATION WITH DIABETIC NEPHROPATHY SUSCEPTIBILITY;

Comprehensive hereditary hemochromatosis genotyping.
Jones D.C.; Young N.T.; Pigott C.; Fuggle S.V.; Barnardo M.C.N.M.; Marshall S.E.; Bunce M.;
Tissue Antigens 60:481-488(2002)
Cited for: VARIANTS HFE1 CYS-65; TYR-282 AND ALA-295;

Identification of new mutations of the HFE, hepcidin, and transferrin receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload.
Biasiotto G.; Belloli S.; Ruggeri G.; Zanella I.; Gerardi G.; Corrado M.; Gobbi E.; Albertini A.; Arosio P.;
Clin. Chem. 49:1981-1988(2003)
Cited for: VARIANTS HFE1 CYS-65; CYS-66; GLY-224 AND TYR-282;

An unusual case of hemochromatosis due to a new compound heterozygosity in HFE (p.[Gly43Asp;His63Asp]+[Cys282Tyr]): structural implications with respect to binding with transferrin receptor 1.
Dupradeau F.-Y.; Pissard S.; Coulhon M.-P.; Cadet E.; Foulon K.; Fourcade C.; Goossens M.; Case D.A.; Rochette J.;
Hum. Mutat. 29:206-206(2008)
Cited for: VARIANTS HFE1 ASP-43 AND TYR-282; VARIANT ASP-63;

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.