MDH2

malate dehydrogenase 2

Basic information

Region (hg38): 7:76048050-76067508

Links

ENSG00000146701 ∙ NCBI:4191 ∙ OMIM:154100 ∙ HGNC:6971 ∙ Uniprot:P40926 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 51 (Moderate), mode of inheritance: AR
• hereditary pheochromocytoma-paraganglioma (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 51 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 51	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; Neurologic	27989324

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MDH2 gene.

• Inborn genetic diseases (401 variants)
• not provided (267 variants)
• Developmental and epileptic encephalopathy, 51 (13 variants)
• Infantile encephalopathy (2 variants)
• not specified (2 variants)
• MDH2-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MDH2 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				166	2	168
missense	1	1	284	4	3	293
nonsense						0
start loss			2			2
frameshift	4		2			6
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	1	2			4
splice region			13	12	2	27
non coding				28	13	41
Total	6	2	291	198	18

Highest pathogenic variant AF is 0.000138

Variants in MDH2

This is a list of pathogenic ClinVar variants found in the MDH2 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-76048162-T-C			Uncertain significance (Sep 29, 2021)
7-76048163-G-A			Uncertain significance (Jul 18, 2022)
7-76048164-C-G		Developmental and epileptic encephalopathy, 51	Uncertain significance (Mar 27, 2019)
7-76048166-C-T		Inborn genetic diseases	Likely benign (Nov 16, 2023)
7-76048169-C-T		Inborn genetic diseases	Likely benign (Oct 21, 2021)
7-76048170-G-A		Inborn genetic diseases	Uncertain significance (Jul 27, 2023)
7-76048172-C-A		Inborn genetic diseases	Likely benign (Apr 06, 2023)
7-76048173-C-G		Inborn genetic diseases	Uncertain significance (Feb 10, 2024)
7-76048176-G-C		Inborn genetic diseases	Uncertain significance (Mar 03, 2022)
7-76048178-C-T		Inborn genetic diseases	Likely benign (Apr 01, 2023)
7-76048179-C-T		Inborn genetic diseases	Uncertain significance (Mar 22, 2023)
7-76048180-G-A			Uncertain significance (Jan 17, 2024)
7-76048180-G-C		Inborn genetic diseases	Uncertain significance (Jul 27, 2023)
7-76048181-G-A		Inborn genetic diseases	Likely benign (May 13, 2023)
7-76048182-C-G		Inborn genetic diseases	Uncertain significance (Jul 07, 2023)
7-76048186-C-T			Benign (Feb 01, 2024)
7-76048187-C-T		Inborn genetic diseases	Likely benign (Apr 28, 2021)
7-76048189-G-C		Inborn genetic diseases	Uncertain significance (May 13, 2023)
7-76048190-C-G		Inborn genetic diseases	Uncertain significance (Nov 27, 2022)
7-76048190-C-T		Inborn genetic diseases	Likely benign (Dec 01, 2023)
7-76048192-C-T		Inborn genetic diseases	Uncertain significance (Apr 26, 2022)
7-76048193-T-A		Inborn genetic diseases	Likely benign (Jun 26, 2020)
7-76048195-C-T		Inborn genetic diseases	Uncertain significance (Oct 30, 2021)
7-76048196-T-C		Inborn genetic diseases	Likely benign (Sep 28, 2023)
7-76048200-C-G		Inborn genetic diseases	Uncertain significance (Mar 30, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MDH2	protein_coding	protein_coding	ENST00000315758	9	19458

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00668	0.977	125713	0	35	125748	0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0254	208	209	0.995	0.0000125	2148
Missense in Polyphen		67	77.941	0.85962		795
Synonymous	-0.521	101	94.6	1.07	0.00000666	712
Loss of Function	2.10	6	14.7	0.409	6.88e-7	176

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000152	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000255	0.000255
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Disease: DISEASE: Epileptic encephalopathy, early infantile, 51 (EIEE51) [MIM:617339]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE51 is an autosomal recessive form characterized by onset of intractable seizures and hypotonia in the first days or weeks of life, and severely delayed psychomotor development. {ECO:0000269|PubMed:27989324}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Citrate cycle (TCA cycle) - Homo sapiens (human);Pyruvate metabolism - Homo sapiens (human);Cysteine and methionine metabolism - Homo sapiens (human);Glyoxylate and dicarboxylate metabolism - Homo sapiens (human);The oncogenic action of Succinate;The oncogenic action of Fumarate;Pyruvate dehydrogenase deficiency (E3);Pyruvate dehydrogenase deficiency (E2);2-ketoglutarate dehydrogenase complex deficiency;Mitochondrial complex II deficiency;Fumarase deficiency;Congenital lactic acidosis;Malate-Aspartate Shuttle;Gluconeogenesis;Citric Acid Cycle;Glycogenosis, Type IA. Von gierke disease;Glycogenosis, Type IC;Glutaminolysis and Cancer;The oncogenic action of 2-hydroxyglutarate;Glycogen Storage Disease Type 1A (GSD1A) or Von Gierke Disease;The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria;The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria ;Triosephosphate isomerase;Fructose-1,6-diphosphatase deficiency;Phosphoenolpyruvate carboxykinase deficiency 1 (PEPCK1);Glycogenosis, Type IB;fig-met-1-last-solution;Amino Acid metabolism;Glycolysis and Gluconeogenesis;TCA Cycle;Metabolism of carbohydrates;Citrate cycle;Citric acid cycle (TCA cycle);Pyruvate metabolism and Citric Acid (TCA) cycle;malate-aspartate shuttle;The citric acid (TCA) cycle and respiratory electron transport;Metabolism;TCA cycle;TCA cycle;gluconeogenesis;superpathway of conversion of glucose to acetyl CoA and entry into the TCA cycle;Gluconeogenesis;Glucose metabolism (Consensus)

Recessive Scores

• pRec: 0.905

Intolerance Scores

• loftool: 0.368
• rvis_EVS: -0.33
• rvis_percentile_EVS: 30.7

Haploinsufficiency Scores

• pHI: 0.323
• hipred: Y
• hipred_score: 0.798
• ghis: 0.525

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mdh2

Gene ontology

• Biological process: gluconeogenesis;tricarboxylic acid cycle;oxaloacetate metabolic process;malate metabolic process;internal protein amino acid acetylation;NADH metabolic process;aerobic respiration
• Cellular component: nucleus;mitochondrion;mitochondrial matrix;membrane;myelin sheath;extracellular exosome
• Molecular function: RNA binding;L-malate dehydrogenase activity;protein self-association;malate dehydrogenase (NADP+) activity