L2HGDH

protein-coding

L-2-hydroxyglutarate dehydrogenase, the group of MicroRNA protein coding host genes

Gene summary

This gene encodes L-2-hydroxyglutarate dehydrogenase, a FAD-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe cognitive disability. [provided by RefSeq, Jul 2008]

Previous symbols:

C14orf160

MANE transcript

NM_024884.3

Inheritance

ClinVar variants

P:47U:154B:72

Top phenotype

L-2-hydroxyglutaric aciduria

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr14:50,237,563-50,312,229

External References & Databases

Ensembl (ENSG00000087299)

Transcript & Mutation Effects

hg38 • Region Span ~74.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *L2HGDH* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 31, 2023. *L2HGDH* encodes L-2-hydroxyglutarate dehydrogenase which acts as a “repair enzyme” responsible for oxidizing L-2-hydroxyglutarate to alpha-ketoglutarate (PMID: 22391998). Accumulation of L-2-hydroxyglutarate has a neurotoxic effect (PMID: 12781789). *L2HGDH* was first reported in relation to autosomal recessive primary mitochondrial disease in 2004 (PMID: 15385440; disease entity first described in 1980; PMID: 6787330), in individuals with central nervous system deterioration including epilepsy and elevated levels of L-2-hydroxyglutaric acid in numerous body fluids (blood, urine, cerebrospinal fluid). While various names have been given to the constellation of features seen in those with *L2HGDH*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *L2HGDH* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight variants (four frameshift, one nonsense, three missense) in six probands from six publications (PMIDs 29980873, 34719772, 25982940, 24573090, 33839641, 16134148). However, more than 100 cases have been reported to date (PMID: 37113859). Of note, individuals with biallelic null variants have been reported. Affected individuals have a generally consistent phenotype with predominant neurologic involvement (intellectual disability, seizures, developmental delay, ataxia movement disorders, spastic paraplegia, white matter disease, basal ganglia lesions) with elevated L-2-hydroxyglutaric acid in urine and other body fluids. This gene-disease association is supported by other genes with a similar biochemical function, RNA expression studies showing high expression of *L2HGDH* in brain, and animal models (mice and canines) which parallel human disease (PMIDs: 34270333, 17475916, 28137912, 15385440). In summary, there is definitive evidence to support the relationship between *L2HGDH* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 31, 2023 (SOP Version 9).

L-2-hydroxyglutaric aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009370

Submitter: G2P

L-2-hydroxyglutaric aciduriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009370

Submitter: Orphanet

L-2-hydroxyglutaric aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009370

Submitter: Labcorp Genetics (formerly Invitae)

L-2-hydroxyglutaric aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009370

Submitter: Ambry Genetics

L-2-hydroxyglutaric aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009370

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

L-2-hydroxyglutaric aciduriaAR

Manifestation: Biochemical; Neurologic; Oncologic

Intervention: Biochemical; Oncologic

Rationale: A low lysine diet has been reported as resulting in clinical and biochemical improvement; An increased risk of cerebral neoplasms has been reported, and awareness may lead to early detection and treatment

Refs: 6787330; 1642474; 7609438; 7609437; 9860123; 10399870; 15548604; 15385440; 15824270; 18931888; 21937992; 22241392; 22353300; 22459673

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to L2HGDH variants in ClinVar

7 Conditions Cataloged

L-2-hydroxyglutaric aciduriaTotal: 248

Inborn genetic diseasesTotal: 75

not providedTotal: 58

not specifiedTotal: 41

L2HGDH-related disorderTotal: 10

L2HGDH-related disordersTotal: 6

Abnormality of metabolism/homeostasisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024884.3. 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	2 clinvar	58 clinvar		61
missense	4 clinvar	11 clinvar	145 clinvar	13 clinvar	1 clinvar	174
nonsense	7 clinvar	3 clinvar	1 clinvar			11
start loss	1 clinvar					1
frameshift	9 clinvar	1 clinvar	2 clinvar			12
splice donor/acceptor (+/-2bp)	4 clinvar	6 clinvar	4 clinvar			14
Total	25	22	154	71	1	273

Highest pathogenic variant AF is 0.00003599158

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024884.3	RefSeq	NP_079160.1	10	MANE Select
ENST00000267436.9	Ensembl	ENSP00000267436.4	10	MANE Select
NM_001425212.1	RefSeq	NP_001412141.1	10	Standard
NM_001425213.1	RefSeq	NP_001412142.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Butanoate metabolism - Homo sapiens (human)
The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria
The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria
Interconversion of 2-oxoglutarate and 2-hydroxyglutarate
Pyruvate metabolism and Citric Acid (TCA) cycle

Biological Process

2-oxoglutarate metabolic process
cellular protein metabolic process
oxidation-reduction process

Molecular Function

(S)-2-hydroxy-acid oxidase activity
2-hydroxyglutarate dehydrogenase activity

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of membrane
integral component of mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000267436
Coding exons: 10
Length: 74986
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 40
Defined: 125748
p: 0.000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.425	235	254	0.925	0.0000124	2972
Missense (PolyPhen)		97	108.8	0.89156		1340
Synonymous	0.705	80	88.4	0.905	0.00000401	935
Loss of Function	2.34	11	23.1	0.475	0.00000129	272

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.159

Intolerance Scores

LoFtool: 0.360
RVIS EVS: 0.02
RVIS percentile EVS: 55.45

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.750

Gene Damage Prediction

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