D2HGDH

D-2-hydroxyglutarate dehydrogenase

Basic information

Region (hg38): 2:241734602-241768816

Links

ENSG00000180902 ∙ NCBI:728294 ∙ OMIM:609186 ∙ HGNC:28358 ∙ Uniprot:Q8N465 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• D-2-hydroxyglutaric aciduria 1 (Limited), mode of inheritance: AR
• D-2-hydroxyglutaric aciduria (Supportive), mode of inheritance: AD
• D-2-hydroxyglutaric aciduria 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
D-2-hydroxyglutaric aciduria 1	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Biochemical; Cardiovascular; Neurologic	15609246; 19169842; 20020533

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the D2HGDH gene.

• D-2-hydroxyglutaric aciduria 1 (9 variants)
• not provided (2 variants)
• D-2-hydroxyglutaric aciduria (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the D2HGDH gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	78	4	84
missense	1	1	107	9		118
nonsense	2					2
start loss						0
frameshift	7	1	1			9
inframe indel			2			2
splice donor/acceptor (+/-2bp)	2	2	2			6
splice region			2	6	1	9
non coding			43	24	41	108
Total	12	4	157	111	45

Highest pathogenic variant AF is 0.0000985

Variants in D2HGDH

This is a list of pathogenic ClinVar variants found in the D2HGDH region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-241734647-C-T		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 12, 2018)
2-241734653-C-A		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 13, 2018)
2-241734656-C-T		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 12, 2018)
2-241734683-G-A		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 13, 2018)
2-241734686-G-A		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 12, 2018)
2-241734689-A-G		D-2-hydroxyglutaric aciduria 1	Benign (Jan 12, 2018)
2-241734690-T-G		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 12, 2018)
2-241734710-C-T		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 13, 2018)
2-241734898-A-C			Benign (May 11, 2021)
2-241734936-C-G			Benign (May 11, 2021)
2-241734937-C-G			Benign (May 11, 2021)
2-241735129-C-G		not specified • D-2-hydroxyglutaric aciduria 1	Conflicting classifications of pathogenicity (Jan 13, 2018)
2-241735131-A-T		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jul 27, 2017)
2-241735134-C-G		D-2-hydroxyglutaric aciduria 1	Benign (May 11, 2021)
2-241735142-C-T		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 13, 2018)
2-241735180-C-T		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 12, 2018)
2-241735188-C-T		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jan 12, 2018)
2-241735230-G-A		D-2-hydroxyglutaric aciduria 1	Likely benign (Aug 15, 2022)
2-241735230-G-GC		D-2-hydroxyglutaric aciduria 1	Likely pathogenic (Mar 29, 2024)
2-241735235-G-T		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Jun 19, 2022)
2-241735253-C-T		D-2-hydroxyglutaric aciduria 1	Uncertain significance (Sep 13, 2022)
2-241735261-C-T		D-2-hydroxyglutaric aciduria 1	Likely benign (Aug 28, 2023)
2-241735263-G-A		D-2-hydroxyglutaric aciduria 1	Likely benign (Jul 28, 2023)
2-241735267-C-A		D-2-hydroxyglutaric aciduria 1	Likely benign (Nov 02, 2023)
2-241735267-C-G		not specified • D-2-hydroxyglutaric aciduria 1	Benign/Likely benign (Jan 30, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
D2HGDH	protein_coding	protein_coding	ENST00000321264	9	34238

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0543	0.945	125715	0	33	125748	0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.718	300	337	0.890	0.0000214	3288
Missense in Polyphen		80	111.33	0.71858		1115
Synonymous	-0.543	172	163	1.05	0.0000119	1138
Loss of Function	2.95	6	20.4	0.295	9.37e-7	223

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000606	0.000605
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000231	0.000231
European (Non-Finnish)	0.0000357	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.000233	0.000229
Other	0.000663	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the oxidation of D-2-hydroxyglutarate to alpha-ketoglutarate. {ECO:0000269|PubMed:15070399}.
• Disease: DISEASE: D-2-hydroxyglutaric aciduria 1 (D2HGA1) [MIM:600721]: A rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine. {ECO:0000269|PubMed:15609246, ECO:0000269|PubMed:16037974, ECO:0000269|PubMed:16081310}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria ;Interconversion of 2-oxoglutarate and 2-hydroxyglutarate;Pyruvate metabolism and Citric Acid (TCA) cycle;The citric acid (TCA) cycle and respiratory electron transport;Metabolism (Consensus)

Recessive Scores

• pRec: 0.142

Intolerance Scores

• loftool: 0.0903
• rvis_EVS: -0.06
• rvis_percentile_EVS: 48.84

Haploinsufficiency Scores

• pHI: 0.261
• hipred: N
• hipred_score: 0.425
• ghis: 0.482

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.171

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: D2hgdh

Gene ontology

• Biological process: 2-oxoglutarate metabolic process;response to manganese ion;response to zinc ion;lactate oxidation;respiratory electron transport chain;response to cobalt ion;response to magnesium ion;cellular protein metabolic process;response to calcium ion
• Cellular component: mitochondrion;mitochondrial matrix;extrinsic component of cytoplasmic side of plasma membrane
• Molecular function: D-lactate dehydrogenase (cytochrome) activity;(R)-2-hydroxyglutarate dehydrogenase activity;FAD binding