UniProtKB/Swiss-Prot Q8N465: Variant p.Gly436Val

D-2-hydroxyglutarate dehydrogenase, mitochondrial
Gene: D2HGDH
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Variant information Variant position:

436 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

US 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 Glycine (G) to Valine (V) at position 436 (G436V, p.Gly436Val). 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 glycine (G) to medium size and hydrophobic (V) 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
Variant description:

Slight reduction in catalytic activity. Any additional useful information about the variant.

Sequence information Variant position:

436 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Protein sequence length:

521 The length of the canonical sequence.
Location on the sequence:

TDLRARLGPHAKHVVGYGHL G DGNLHLNVTAEAFSPSLLAA 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                         TDLRARLGPHAKHVVGYGHLGDGNLHLNVTAEAFSPSLLAA

Mouse                         IDLRTRLGPRAKHVVGYGHLGDGNLHLNVTAEAFSRELLGA

Rat                           IDLRTRLGPRAKHVVGYGHLGDGNLHLNVTAEAFSQELLGA

Bovine                        GDLRARLGPSAKHVVGYGHLGDGNLHLNVTSEAFSTSLLGA

Zebrafish                     QDMRRHLGGMAKNVVGYGHVGDGNLHLNITSPSKDFDLLAA

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	14 – 521	D-2-hydroxyglutarate dehydrogenase, mitochondrial
Binding site	434 – 434
Binding site	441 – 441
Binding site	443 – 443
Alternative sequence	314 – 521	Missing. In isoform 2.
Alternative sequence	320 – 521	Missing. In isoform 3.
Mutagenesis	434 – 434	H -> A. Loss of catalytic activity.
Mutagenesis	441 – 441	H -> A. Loss of catalytic activity.
Mutagenesis	443 – 443	N -> A. Significantly reduced catalytic activity.
Helix	435 – 437

Literature citations
D-2-Hydroxyglutaric aciduria in three patients with proven SSADH deficiency: genetic coincidence or a related biochemical epiphenomenon?
Struys E.A.; Verhoeven N.M.; Salomons G.S.; Berthelot J.; Vianay-Saban C.; Chabrier S.; Thomas J.A.; Tsai A.C.-H.; Gibson K.M.; Jakobs C.;
Mol. Genet. Metab. 88:53-57(2006)
Cited for: VARIANTS GLY-15 AND VAL-436; CATALYTIC ACTIVITY; Structure, substrate specificity, and catalytic mechanism of human D-2-HGDH and insights into pathogenicity of disease-associated mutations.
Yang J.; Zhu H.; Zhang T.; Ding J.;
Cell Discov. 7:3-3(2021)
Cited for: X-RAY CRYSTALLOGRAPHY (2.21 ANGSTROMS) OF 51-521 IN COMPLEX WITH D-2-HYDROXYGLUTARATE; D-MALATE; D-LACTATE; L-2-HYDROXYGLUTARATE AND 2-OXOGLUTARATE; FUNCTION; CATALYTIC ACTIVITY; ZINC-BINDING SITES; BIOPHYSICOCHEMICAL PROPERTIES; MUTAGENESIS OF ARG-386; THR-390; LYS-401; HIS-434; HIS-441; ASN-443; GLU-475 AND HIS-476; CHARACTERIZATION OF VARIANTS D2HGA1 TRP-109; LYS-127; VAL-131; SER-147; THR-153; VAL-153; TYR-172; LEU-189; VAL-205; VAL-231; SER-233; TYR-375; MET-399; HIS-419; THR-426; ASP-439; ALA-444; VAL-446 AND ARG-477; CHARACTERIZATION OF VARIANT VAL-436;

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