UniProtKB/Swiss-Prot P04062: Variant p.Asp448His

Glucosylceramidase
Gene: GBA
Chromosomal location: 1q21
Variant information

Variant position:  448
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 have been found in patients and disease-association is reported in literature. However, this classification is not a definitive assessment of variant pathogenicity.
  • Polymorphism: No disease-association has been reported.
  • Unclassified: Variants have been found in patients but disease-association remains unclear.

Residue change:  From Aspartate (D) to Histidine (H) at position 448 (D448H, p.Asp448His).
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 acidic (D) to medium size and polar (H)
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:  Gaucher disease (GD) [MIM:230800]: A lysosomal storage disease due to deficient activity of beta-glucocerebrosidase and characterized by accumulation of glucosylceramide in the reticulo-endothelial system. Different clinical forms are recognized depending on the presence (neuronopathic forms) or absence of central nervous system involvement, severity and age of onset. 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 GD; type 1 and type neuronopathic; at homozygosity it causes GD3C; also found in a patient with Parkinson disease; gene conversion; very low activity; alters protein stability.
Any additional useful information about the variant.

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



Sequence information

Variant position:  448
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  536
The length of the canonical sequence.

Location on the sequence:   GGPNWVRNFVDSPIIVDITK  D TFYKQPMFYHLGHFSKFIPE
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                         GGPNWVRNFVDSPIIVDITKDTFYKQPMFYHLGHFSKFIPE

Chimpanzee                    GGPNWVRNFVDSPIIVDITKDTFYKQPMFYHLGHFSKFIPE

Mouse                         GGPNWVRNFVDSPIIVDIPKDAFYKQPMFYHLGHFSKFIPE

Pig                           GGPNWVRNFVDSPIIVDISKDTFYKQPMFYHLGHFSKFIPE

Bovine                        GGPNWVRNFVDSPIIVDIAKDTFYKQPMFYHLGHFSKFIPE

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 40 – 536 Glucosylceramidase
Alternative sequence 425 – 536 Missing. In isoform 3.


Literature citations

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease.
Neumann J.; Bras J.; Deas E.; O'Sullivan S.S.; Parkkinen L.; Lachmann R.H.; Li A.; Holton J.; Guerreiro R.; Paudel R.; Segarane B.; Singleton A.; Lees A.; Hardy J.; Houlden H.; Revesz T.; Wood N.W.;
Brain 132:1783-1794(2009)
Cited for: INVOLVEMENT IN PARKINSON DISEASE; VARIANTS GLU-46; CYS-170; GLU-232; GLN-296; SER-409; ALA-419; HIS-448; ASN-482; PRO-483; PRO-495; LEU-497 AND CYS-502;

Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.
Liou B.; Kazimierczuk A.; Zhang M.; Scott C.R.; Hegde R.S.; Grabowski G.A.;
J. Biol. Chem. 281:4242-4253(2006)
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 40-536; CHARACTERIZATION OF VARIANTS GD SER-55; GLN-87; ASN-118; GLN-159; LEU-161; VAL-162; VAL-166; ASN-200; PHE-213; PHE-224; GLU-232; GLU-237; LEU-298; ILE-303; CYS-343; ILE-362; LYS-365; GLY-381; LYS-388; TRP-392; CYS-402; SER-409; VAL-410; HIS-419; LYS-421; ARG-429; LEU-433; SER-436; ASN-438; HIS-448; VAL-455; PRO-483; PRO-500 AND PRO-502; MUTAGENESIS OF CYS-43; CYS-57 AND CYS-62;

Gaucher disease in Spanish patients: analysis of eight mutations.
Cormand B.; Vilageliu L.; Burguera J.M.; Balcells S.; Gonzalez-Duarte R.; Grinberg D.; Chabas A.;
Hum. Mutat. 5:303-309(1995)
Cited for: VARIANTS GD SER-409; HIS-448; PRO-483 AND CYS-502;

Mutation prevalence among 47 unrelated Japanese patients with Gaucher disease: identification of four novel mutations.
Ida H.; Rennert O.M.; Kawame H.; Maekawa K.; Eto Y.;
J. Inherit. Metab. Dis. 20:67-73(1997)
Cited for: VARIANTS GD VAL-228; ILE-252; GLY-405; HIS-448; GLN-452; PRO-483 AND CYS-535;

D409H/D409H genotype in Gaucher-like disease.
Uyama E.; Uchino M.; Ida H.; Eto Y.; Owada M.;
J. Med. Genet. 34:175-175(1997)
Cited for: VARIANT PSEUDO-GAUCHER HIS-448;

Glucocerebrosidase mutations among Chinese neuronopathic and non-neuronopathic Gaucher disease patients.
Choy F.Y.M.; Wong K.; Shi H.P.;
Am. J. Med. Genet. 84:484-486(1999)
Cited for: VARIANTS GD ARG-241; CYS-244; ILE-252; HIS-448 AND PRO-483;

Detection of three rare (G377S, T134P and 1451delAC), and two novel mutations (G195W and Rec[1263del55;1342G>C]] in Spanish Gaucher disease patients.
Sarria A.J.; Giraldo P.; Perez-Calvo J.I.; Pocovi M.;
Hum. Mutat. 14:88-88(1999)
Cited for: VARIANTS GD PRO-173; TRP-234; SER-409; SER-416; HIS-448 AND PRO-483;

Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.
Koprivica V.; Stone D.L.; Park J.K.; Callahan M.; Frisch A.; Cohen I.J.; Tayebi N.; Sidransky E.;
Am. J. Hum. Genet. 66:1777-1786(2000)
Cited for: VARIANTS GD TRP-87; ASN-118; THR-129; ASP-156; GLN-159; TRP-159; LEU-170; ILE-173; CYS-209; PRO-209; SER-227; THR-229; PRO-235; ARG-241; ILE-252; GLN-296; CYS-324; THR-380; MET-408; SER-409; SER-416; LEU-433; TYR-438; HIS-448; PRO-483 AND CYS-502; VARIANT LYS-365;

Variant Gaucher disease characterized by dysmorphic features, absence of cardiovascular involvement, laryngospasm, and compound heterozygosity for a novel mutation (D409H/C16S).
Bodamer O.A.F.; Church H.J.; Cooper A.; Wraith J.E.; Scott C.R.; Scaglia F.;
Am. J. Med. Genet. 109:328-331(2002)
Cited for: VARIANTS GD SER-55 AND HIS-448;

Identification and functional characterization of five novel mutant alleles in 58 Italian patients with Gaucher disease type 1.
Miocic S.; Filocamo M.; Dominissini S.; Montalvo A.L.; Vlahovicek K.; Deganuto M.; Mazzotti R.; Cariati R.; Bembi B.; Pittis M.G.;
Hum. Mutat. 25:100-100(2005)
Cited for: VARIANTS GD1 ASN-63; SER-158; TRP-159; CYS-170; LEU-221; GLU-230; ARG-241; GLN-294; CYS-324; SER-409; ASN-438; LEU-440; HIS-448; CYS-457; ASP-460; PRO-483 AND ARG-490; CHARACTERIZATION OF VARIANTS GD1 ASN-63; SER-158; LEU-221; GLU-230 AND ASP-460;

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.