MDH1

protein-coding

malate dehydrogenase 1

Gene summary

This gene encodes an enzyme that catalyzes the NAD/NADH-dependent, reversible oxidation of malate to oxaloacetate in many metabolic pathways, including the citric acid cycle. Two main isozymes are known to exist in eukaryotic cells: one is found in the mitochondrial matrix and the other in the cytoplasm. This gene encodes the cytosolic isozyme, which plays a key role in the malate-aspartate shuttle that allows malate to pass through the mitochondrial membrane to be transformed into oxaloacetate for further cellular processes. Alternatively spliced transcript variants have been found for this gene. A recent study showed that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is localized in the peroxisomes. Pseudogenes have been identified on chromosomes X and 6. [provided by RefSeq, Feb 2016]

MANE transcript

NM_005917.4

Inheritance

ClinVar variants

P:1U:38B:8

Top phenotype

Developmental and epileptic encephalopathy 88

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr2:63,588,609-63,607,197

External References & Databases

Ensembl (ENSG00000014641)

Transcript & Mutation Effects

hg38 • Region Span ~18.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 88LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030072

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 88MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030072

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 88LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030072

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 88AR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: 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

Refs: 31538237

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MDH1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 36

not providedTotal: 9

Developmental and epileptic encephalopathy, 88Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005917.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	6 clinvar		7
missense	1 clinvar		32 clinvar	2 clinvar		35
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	1	0	38	8	0	47

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 86 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005917.4	RefSeq	NP_005908.1	9	MANE Select
ENST00000233114.13	Ensembl	ENSP00000233114.8	9	MANE Select
NM_001199111.2	RefSeq	NP_001186040.1	9	Standard
NM_001199112.2	RefSeq	NP_001186041.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

gluconeogenesis
tricarboxylic acid cycle
oxaloacetate metabolic process
malate metabolic process
NADH metabolic process

Molecular Function

malic enzyme activity
protein binding
L-malate dehydrogenase activity
diiodophenylpyruvate reductase activity
NAD binding

Cellular Component

extracellular space
cytosol
myelin sheath
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000539945
Coding exons: 9
Length: 18589
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125748
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.18	141	186	0.757	0.00000924	2298
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.621

Intolerance Scores

LoFtool: 0.0617
RVIS EVS: -0.21
RVIS percentile EVS: 38.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

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