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UniProtKB/Swiss-Prot Q8N465: Variant p.Gly477Arg

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

Variant position:  477
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 Arginine (R) at position 477 (G477R, p.Gly477Arg).
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 large size and basic (R)
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

Variant description:  In D2HGA1; unknown pathological significance; almost complete loss of catalytic activity.
Any additional useful information about the variant.



Sequence information

Variant position:  477
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:   LEPHVYEWTAGQQGSVSAEH  G VGFRKRDVLGYSKPPGALQL
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                         LEPHVYEWTAGQQGSVSAEHGVGFRKRDVLGYSKPPGALQL

Mouse                         LEPYVYAWTAEQRGSVSAEHGLGFKKKDVLGYSKPPVAVTL

Rat                           LEPYVYAWTAEQRGSVSAEHGLGFKKKNVLGYSKPPVAVKL

Bovine                        LEPYVYEWTAGQRGSVSAEHGLGFKKKDVLGYSKPPEALQL

Zebrafish                     IEPYVYEWTSQWKGSISAEHGLGLKKRNYIYYSKPSEAVAL

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 14 – 521 D-2-hydroxyglutarate dehydrogenase, mitochondrial
Metal binding 475 – 475 Zinc
Binding site 476 – 476 D-2-hydroxyglutarate
Binding site 476 – 476 D-lactate
Binding site 476 – 476 D-malate
Alternative sequence 314 – 521 Missing. In isoform 2.
Alternative sequence 320 – 521 Missing. In isoform 3.
Mutagenesis 475 – 475 E -> A. Loss of catalytic activity.
Mutagenesis 476 – 476 H -> A. Loss of catalytic activity.


Literature citations

Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria.
Kranendijk M.; Struys E.A.; Gibson K.M.; Wickenhagen W.V.; Abdenur J.E.; Buechner J.; Christensen E.; de Kremer R.D.; Errami A.; Gissen P.; Gradowska W.; Hobson E.; Islam L.; Korman S.H.; Kurczynski T.; Maranda B.; Meli C.; Rizzo C.; Sansaricq C.; Trefz F.K.; Webster R.; Jakobs C.; Salomons G.S.;
Hum. Mutat. 31:279-283(2010)
Cited for: VARIANTS D2HGA1 TRP-109; LYS-127; VAL-131; SER-147; THR-153; VAL-153; 169-GLN--ALA-521 DEL; TYR-172; LEU-189; VAL-205; VAL-231; SER-233; TYR-375; MET-399; 400-TYR--ALA-521 DEL; HIS-419; THR-426; ASP-439; ALA-444; VAL-446 AND ARG-477; CHARACTERIZATION OF VARIANTS D2HGA1 TRP-109; VAL-153; TYR-172; 400-TYR--ALA-521 DEL; HIS-419 AND THR-426; FUNCTION; 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;

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.