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UniProtKB/Swiss-Prot Q8N465: Variant p.Asp375Tyr

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

Variant position:  375
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 Aspartate (D) to Tyrosine (Y) at position 375 (D375Y, p.Asp375Tyr).
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 acidic (D) to large size and aromatic (Y)
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:  In D2HGA1; unknown pathological significance; moderate reduction in catalytic activity.
Any additional useful information about the variant.

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



Sequence information

Variant position:  375
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:   GHFLEHALGSGLVTDGTMAT  D QRKVKMLWALRERITEALSR
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                         GHFLEHALGSGLVTDGTMATDQRKVKMLWALRERITEALSR

Mouse                         TNVLEQVLNSGLVTDGTMATDQRKVQMLWALRERITEALSR

Rat                           TNVLEQVLNSGLVIDGTMATDQRKVQMLWALRERITEALSR

Bovine                        GCFLEQVLDSGLVTDGTLGSDERRIKMLWALRERITEALSR

Zebrafish                     HQFLEEVMTSSLVTDGTVATEATKIKALWSLRERVTEALTH

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
Binding site 386 – 386 D-2-hydroxyglutarate
Binding site 386 – 386 D-lactate
Binding site 386 – 386 D-malate
Binding site 390 – 390 D-2-hydroxyglutarate
Binding site 390 – 390 D-malate
Alternative sequence 314 – 521 Missing. In isoform 2.
Alternative sequence 320 – 521 Missing. In isoform 3.
Mutagenesis 386 – 386 R -> A. Loss of catalytic activity.
Mutagenesis 390 – 390 T -> A. Significantly reduced catalytic activity.


Literature citations

Phenotypic heterogeneity in the presentation of D-2-hydroxyglutaric aciduria in monozygotic twins.
Misra V.K.; Struys E.A.; O'brien W.; Salomons G.S.; Glover T.; Jakobs C.; Innis J.W.;
Mol. Genet. Metab. 86:200-205(2005)
Cited for: VARIANT D2HGA1 TYR-375;

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.