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UniProtKB/Swiss-Prot Q9H3L0: Variant p.Leu259Pro

Methylmalonic aciduria and homocystinuria type D protein, mitochondrial
Gene: MMADHC
Chromosomal location: 2q23
Variant information

Variant position:  259
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 Leucine (L) to Proline (P) at position 259 (L259P, p.Leu259Pro).
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:  -3
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:  Methylmalonic aciduria and homocystinuria, cblD type (MAHCD) [MIM:277410]: An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinical features include developmental delay, hyotonia, mental retardation, seizures, megaloblastic anemia. Some patients manifest combined methylmalonic aciduria and homocystinuria (referred to as cblD original), some have only isolated homocystinuria (cblD variant 1), and others have only methylmalonic aciduria (cblD variant 2). {ECO:0000269|PubMed:18385497, ECO:0000269|PubMed:24722857, ECO:0000269|PubMed:26483544}. 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 MAHCD; cblD variant 1; decreases methylcobalamin levels and increases adenosylcobalamin levels; no effect on interaction with MMACHC.
Any additional useful information about the variant.

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



Sequence information

Variant position:  259
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  296
The length of the canonical sequence.

Location on the sequence:   NNTLFETDERYRHLGFSVDD  L GCCKVIRHSLWGTHVVVGSI
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                         NNTLFETDERYRHLGFSVDDLGCCKVIRHSLWGTHVVVGSI

Mouse                         NNTLFETDERYRHLGFSVDDLGCCKVIRHSLWGTHVVVGSI

Rat                           NNTLFETDERYRHLGFSVDDLGCCKVIRHGLWGTHVVVGSI

Chicken                       NNTLFETDERYRHFGFSVDDLGCCKVIRHNIWGTHVVVGSI

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 39 – 296 Methylmalonic aciduria and homocystinuria type D protein, mitochondrial
Mutagenesis 266 – 266 R -> A. Mildly decreases methylcobalamin levels and strongly increases adenosylcobalamin levels.
Mutagenesis 270 – 270 W -> A. Decreases methylcobalamin levels.
Mutagenesis 278 – 278 S -> A. Marginally decreases methylcobalamin levels and strongly increases adenosylcobalamin levels.


Literature citations

Gene identification for the cblD defect of vitamin B12 metabolism.
Coelho D.; Suormala T.; Stucki M.; Lerner-Ellis J.P.; Rosenblatt D.S.; Newbold R.F.; Baumgartner M.R.; Fowler B.;
N. Engl. J. Med. 358:1454-1464(2008)
Cited for: FUNCTION; TISSUE SPECIFICITY; VARIANTS MAHCD LEU-ALA-GLU-PRO-LEU-SER-108 INS; ASN-182; 204-PHE--ALA-232 DEL; CYS-249 AND PRO-259;

Characterization of functional domains of the cblD (MMADHC) gene product.
Jusufi J.; Suormala T.; Burda P.; Fowler B.; Froese D.S.; Baumgartner M.R.;
J. Inherit. Metab. Dis. 37:841-849(2014)
Cited for: FUNCTION; CHARACTERIZATION OF VARIANT MAHCD PRO-259; MUTAGENESIS OF PHE-165; MET-186; TRP-189; ARG-197; PHE-204; CYS-212; ASP-226; TYR-237; ARG-266; TRP-270; SER-278 AND PHE-280;

Structural insights into the MMACHC-MMADHC protein complex involved in vitamin B12 trafficking.
Froese D.S.; Kopec J.; Fitzpatrick F.; Schuller M.; McCorvie T.J.; Chalk R.; Plessl T.; Fettelschoss V.; Fowler B.; Baumgartner M.R.; Yue W.W.;
J. Biol. Chem. 290:29167-29177(2015)
Cited for: INTERACTION WITH MMACHC; CHARACTERIZATION OF VARIANTS MAHCD ASN-182 AND PRO-259; MUTAGENESIS OF TRP-189 AND ASP-226;

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.