UniProtKB/SwissProt variant VAR

Variant information

Variant position:

402

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 Arginine (R) to Tryptophan (W) at position 402 (R402W, p.Arg402Trp).

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 large size and basic (R) to large size and aromatic (W)

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:

Glutaric aciduria 1 (GA1) [MIM:231670]: An autosomal recessive metabolic disorder characterized by progressive dystonia and athetosis due to gliosis and neuronal loss in the basal ganglia. {ECO:0000269|PubMed:14707522, ECO:0000269|PubMed:18775954, ECO:0000269|PubMed:24973495, ECO:0000269|PubMed:8541831, ECO:0000269|PubMed:8900227, ECO:0000269|PubMed:8900228, ECO:0000269|PubMed:9600243}. 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 GA1; most common mutation identified; loss of tetramerization; loss enzyme activity.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs121434369 [ dbSNP | Ensembl ]

Sequence information

Variant position:

402

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

Protein sequence length:

438

The length of the canonical sequence.

Location on the sequence:

ARQARDMLGGNGISDEYHVI R HAMNLEAVNTYEGTHDIHAL

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                         ARQARDMLGGNGISDEYHVIRHAMNLEAVNTYEGTHDIHAL

Mouse                         ARQARDILGGNGISDEYHVIRHAMNLEAVNTYEGTHDIHAL

Bovine                        ARQARDMLGGNGISDEYHVIRHVMNLESVNTYEGTHDIHAL

Caenorhabditis elegans        ARKARDMLGGNGIVDEYHIMRHMVNLETVNTYEGTHDVHAL

Slime mold                    ARQSRDMLGGNGIADEYHVIRHAANLETVNTYEGTHDIHAL

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.

Type	Positions	Description
Chain	45 – 438	Glutaryl-CoA dehydrogenase, mitochondrial
Active site	414 – 414	Proton acceptor
Binding site	415 – 415	Substrate; via amide nitrogen
Mutagenesis	414 – 414	E -> D. Reduced catalytic activity.
Helix	400 – 410

Literature citations

Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH).
Keyser B.; Muehlhausen C.; Dickmanns A.; Christensen E.; Muschol N.; Ullrich K.; Braulke T.;
Hum. Mol. Genet. 17:3854-3863(2008)
Cited for: CHARACTERIZATION OF VARIANTS GA1 GLY-138; TRP-402 AND LYS-414; SUBUNIT;

Molecular analysis of Cypriot patients with Glutaric aciduria type I: Identification of two novel mutations.
Georgiou T.; Nicolaidou P.; Hadjichristou A.; Ioannou R.; Dionysiou M.; Siama E.; Chappa G.; Anastasiadou V.; Drousiotou A.;
Clin. Biochem. 47:1300-1305(2014)
Cited for: VARIANTS GA1 ASP-64; VAL-268; ARG-375; TRP-402 AND MET-429;

UniProtKB/Swiss-Prot Q92947: Variant p.Arg402Trp