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UniProtKB/Swiss-Prot Q30201: Variant p.His63Asp

Hereditary hemochromatosis protein
Gene: HFE
Variant information

Variant position:  63
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 Histidine (H) to Aspartate (D) at position 63 (H63D, p.His63Asp).
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 (H) to medium size and acidic (D)
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

Polymorphism:  Genetic variations in HFE define the transferrin serum level quantitative trait locus 2 (TFQTL2) [MIM:614193]. Iron is essential for biochemical functions such as oxygen transport and oxidative phosphorylation. Excessive iron can cause iron-overload-related liver diseases, whereas iron deficiency can lead to anemia. Iron status can be assessed by measuring the levels of serum iron, serum transferrin, transferrin saturation with iron, and serum ferritin.
Additional information on the polymorphism described.

Variant description:  Associated with hemochromatosis and variegate porphyria; increased frequency among patients with diabetic nephropathy.
Any additional useful information about the variant.

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



Sequence information

Variant position:  63
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:   GLSLFEALGYVDDQLFVFYD  H ESRRVEPRTPWVSSRISSQM
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                         GLSLFEALGYVDDQLFVFYDHESRRVEPRTPWVSSRISSQM

Chimpanzee                    GLSLFEALGYVDDQLFVFYDHESRRVEPRTPWVSSRISSQM

Mouse                         GLPLFEARGYVDDQLFVSYNHESRRAEPRAPWILEQTSSQL

Rat                           GLPFFEALGYVDDQLFVSYNHESRRAEPRAPWILGQTSSQL

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
Region 23 – 114 Alpha-1
Alternative sequence 26 – 114 RSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVFYDHESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNHSKE -> Q. In isoform 2 and isoform 4.
Alternative sequence 27 – 298 Missing. In isoform 11.
Alternative sequence 27 – 206 Missing. In isoform 6.
Beta strand 56 – 65


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;

High prevalence of the His63Asp HFE mutation in Italian patients with porphyria cutanea tarda.
Sampietro M.; Piperno A.; Lupica L.; Arosio C.; Vergani A.; Corbetta N.; Malosio I.; Mattioli M.; Fracanzani A.L.; Cappellini M.D.; Fiorelli G.; Fargion S.;
Hepatology 27:181-184(1998)
Cited for: VARIANT ASP-63;

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;

Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria.
de Villiers J.N.P.; Hillermann R.; Loubser L.; Kotze M.J.;
Hum. Mol. Genet. 8:1517-1522(1999)
Cited for: VARIANTS HFE1 HIS-127 AND MET-330; VARIANTS MET-53; MET-59 AND 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;

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.