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UniProtKB/Swiss-Prot P50747: Variant p.Val333Glu

Biotin--protein ligase
Gene: HLCS
Variant information

Variant position:  333
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 Glutamate (E) at position 333 (V333E, p.Val333Glu).
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 hydrophobic (V) to medium size and acidic (E)
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:  Holocarboxylase synthetase deficiency (HLCS deficiency) [MIM:253270]: A neonatal form of multiple carboxylase deficiency, an autosomal recessive disorder of biotin metabolism, characterized by ketoacidosis, hyperammonemia, excretion of abnormal organic acid metabolites, and dermatitis. In holocarboxylase synthetase deficiency, clinical and biochemical symptoms improve dramatically with administration of biotin. {ECO:0000269|PubMed:10190325, ECO:0000269|PubMed:10590022, ECO:0000269|PubMed:11735028, ECO:0000269|PubMed:12124727, ECO:0000269|PubMed:12633764, ECO:0000269|PubMed:16134170, ECO:0000269|PubMed:20095979, ECO:0000269|PubMed:25690727, ECO:0000269|PubMed:7842009, ECO:0000269|PubMed:8541348, ECO:0000269|PubMed:8817339, ECO:0000269|PubMed:9396568}. 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 HLCS deficiency; <10% activity; has normal or low KM values for biotin (non-KM mutant).
Any additional useful information about the variant.

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



Sequence information

Variant position:  333
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  726
The length of the canonical sequence.

Location on the sequence:   DRMIVHVPFGTRGGEAVLCQ  V HLELPPSSNIVQTPEDFNLL
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                         DRMIVHVPFGTRGGEAVLCQVHLELPPSSNIVQTPEDFNLL-------

Mouse                         DKMIVHVPFGTLGGEAVLCQVHLELPPGASLVQTADDFNVL

Baker's yeast                 PAAVVLCTVGR--GKVLLTGPHPEF--NVRFMRKSTDKHFL

Fission yeast                 SAAIIYVKVGK--GNVVLTGIHPEF--------SAEGSPIL

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 – 726 Biotin--protein ligase


Literature citations

Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency.
Yang X.; Aoki Y.; Li X.; Sakamoto O.; Hiratsuka M.; Kure S.; Taheri S.; Christensen E.; Inui K.; Kubota M.; Ohira M.; Ohki M.; Kudoh J.; Kawasaki K.; Shibuya K.; Shintani A.; Asakawa S.; Minoshima S.; Shimizu N.; Narisawa K.; Matsubara Y.; Suzuki Y.;
Hum. Genet. 109:526-534(2001)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS HLCS DEFICIENCY ASP-42; PRO-237; GLU-333; SER-360; CYS-456; SER-470; TRP-508; GLY-547; MET-550; SER-581; THR-610 DEL AND TYR-634; CHARACTERIZATION OF VARIANTS HLCS DEFICIENCY ASP-42; SER-360; CYS-456; SER-470; GLY-547 AND TYR-634;

Identification and characterization of mutations in patients with holocarboxylase synthetase deficiency.
Aoki Y.; Li X.; Sakamoto O.; Hiratsuka M.; Akaishi H.; Xu L.; Briones P.; Suormala T.; Baumgartner E.R.; Suzuki Y.; Narisawa K.;
Hum. Genet. 104:143-148(1999)
Cited for: VARIANTS HLCS DEFICIENCY GLU-333; ILE-462; ASN-571; SER-581 AND THR-610 DEL;

Relationship between kinetic properties of mutant enzyme and biochemical and clinical responsiveness to biotin in holocarboxylase synthetase deficiency.
Sakamoto O.; Suzuki Y.; Li X.; Aoki Y.; Hiratsuka M.; Suormala T.; Baumgartner E.R.; Gibson K.M.; Narisawa K.;
Pediatr. Res. 46:671-676(1999)
Cited for: VARIANTS HLCS DEFICIENCY PRO-183; ARG-216; PRO-237; GLU-333; ASP-363; SER-581 AND THR-610 DEL; CHARACTERIZATION OF VARIANTS HLCS DEFICIENCY PRO-183; ARG-216; PRO-237; GLU-333; ASP-363; SER-581 AND THR-610 DEL; FUNCTION; CATALYTIC ACTIVITY; BIOPHYSICOCHEMICAL PROPERTIES;

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.