MDH1

malate dehydrogenase 1

Basic information

Region (hg38): 2:63588608-63607197

Links

ENSG00000014641 ∙ NCBI:4190 ∙ OMIM:154200 ∙ HGNC:6970 ∙ Uniprot:P40925 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 88 (Limited), mode of inheritance: AR
• developmental and epileptic encephalopathy, 88 (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 88	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	Craniofacial; Neurologic	31538237

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MDH1 gene.

• Inborn genetic diseases (8 variants)
• not provided (7 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MDH1 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				4		4
missense			9			9
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				1		1
non coding				1		1
Total	0	0	9	5	0

Variants in MDH1

This is a list of pathogenic ClinVar variants found in the MDH1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-63588667-A-C		Bardet-Biedl syndrome	Likely benign (Jun 14, 2016)
2-63589041-A-G			Likely benign (Jun 01, 2023)
2-63589341-G-C		not specified	Uncertain significance (Dec 07, 2023)
2-63589392-A-G			Likely benign (Mar 01, 2024)
2-63594551-A-G		not specified	Uncertain significance (Mar 21, 2022)
2-63595434-T-C			Likely benign (Oct 01, 2023)
2-63597394-C-A			Likely benign (Jun 01, 2022)
2-63597407-G-A			Uncertain significance (Jun 01, 2022)
2-63597424-C-T			Likely benign (Mar 01, 2023)
2-63597539-G-A		not specified	Uncertain significance (Nov 08, 2022)
2-63597556-C-T			Likely benign (Sep 01, 2023)
2-63597558-C-T		Developmental and epileptic encephalopathy, 88	Pathogenic (Mar 03, 2021)
2-63605301-G-A		not specified	Uncertain significance (Oct 25, 2022)
2-63605370-G-A		not specified	Uncertain significance (Dec 28, 2023)
2-63605391-G-C		not specified	Uncertain significance (Jan 10, 2023)
2-63605954-A-G		not specified	Uncertain significance (Jul 06, 2021)
2-63605964-T-C		not specified	Uncertain significance (Jan 02, 2024)
2-63605996-G-C		not specified	Uncertain significance (Aug 13, 2021)
2-63606007-C-T			Likely benign (Oct 01, 2022)
2-63606899-A-C		not specified	Uncertain significance (Oct 12, 2021)
2-63606913-G-A		not specified	Uncertain significance (Aug 08, 2023)
2-63606944-C-T		not specified	Uncertain significance (May 25, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MDH1	protein_coding	protein_coding	ENST00000539945	9	18589

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.928	0.0723	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.18	141	186	0.757	0.00000924	2298
Missense in Polyphen		55	79.175	0.69467		941
Synonymous	0.604	61	67.3	0.906	0.00000342	689
Loss of Function	3.40	2	17.2	0.116	8.77e-7	211

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000867	0.0000867
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000547	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000264	0.0000264
Middle Eastern	0.0000547	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Pathway: Citrate cycle (TCA cycle) - Homo sapiens (human);Pyruvate metabolism - Homo sapiens (human);Proximal tubule bicarbonate reclamation - Homo sapiens (human);Cysteine and methionine metabolism - Homo sapiens (human);Glyoxylate and dicarboxylate metabolism - Homo sapiens (human);Warburg Effect;Pyruvate Dehydrogenase Complex Deficiency;Transfer of Acetyl Groups into Mitochondria;Primary hyperoxaluria II, PH2;Pyruvate kinase deficiency;Leigh Syndrome;Pyruvate Metabolism;Pyruvate Decarboxylase E1 Component Deficiency (PDHE1 Deficiency);Sterol Regulatory Element-Binding Proteins (SREBP) signalling;TCA Cycle and Deficiency of Pyruvate Dehydrogenase complex (PDHc);Amino Acid metabolism;Pathways in clear cell renal cell carcinoma;Glycolysis and Gluconeogenesis;Metabolism of carbohydrates;Citrate cycle;malate-aspartate shuttle;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: 0.621

Intolerance Scores

• loftool: 0.0617
• rvis_EVS: -0.21
• rvis_percentile_EVS: 38.28

Haploinsufficiency Scores

• pHI: 0.188
• hipred: Y
• hipred_score: 0.582
• ghis: 0.647

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.991

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Mdh1
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); homeostasis/metabolism phenotype

Gene ontology

• Biological process: gluconeogenesis;tricarboxylic acid cycle;oxaloacetate metabolic process;malate metabolic process;NADH metabolic process
• Cellular component: extracellular space;cytosol;myelin sheath;extracellular exosome
• Molecular function: malic enzyme activity;protein binding;L-malate dehydrogenase activity;diiodophenylpyruvate reductase activity;NAD binding