L2HGDH

Chr 14AR

L-2-hydroxyglutarate dehydrogenase

Also known as: C14orf160, L2HGA

NCBI Gene: 79944ENSG00000087299UniProt: Q9H9P8

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]

Primary Disease Associations & Inheritance

L-2-hydroxyglutaric aciduriaMIM #236792
AR
345
ClinVar variants
58
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— L2HGDH
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
58 Pathogenic / Likely Pathogenic· 154 VUS of 345 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.79LOEUF
pLI 0.000
Z-score 2.34
OE 0.48 (0.30–0.79)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.42Z-score
OE missense 0.93 (0.83–1.03)
235 obs / 254.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.48 (0.30–0.79)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.83–1.03)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 11 / 23.1Missense obs/exp: 235 / 254.0Syn Z: 0.70

ClinVar Variant Classifications

345 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41
Likely Pathogenic17
VUS154
Likely Benign95
Benign22
Conflicting16
41
Pathogenic
17
Likely Pathogenic
154
VUS
95
Likely Benign
22
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
6
23
0
41
Likely Pathogenic
6
8
2
1
17
VUS
3
133
16
2
154
Likely Benign
0
5
37
53
95
Benign
0
1
21
0
22
Conflicting
—16
Total211539956345

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

L2HGDH · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

L2HGDH-related L-2-hydroxyglutaric aciduria

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

L-2-hydroxyglutaric aciduria

MIM #236792

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — L2HGDH
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study.
Steenweg ME et al.·Hum Mutat
2010Review
A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family.
Muzammal M et al.·Metab Brain Dis
2022
Identification of novel L2HGDH mutation in a large consanguineous Pakistani family- a case report.
Ullah MI et al.·BMC Med Genet
2018Case report
A Pathogenic L2HGDH Variant Impairs Mitochondrial Targeting and Enzyme Function in L-2-Hydroxyglutaric Aciduria: Clinical and Functional Evidence from Two Affected Siblings.
Guo Q et al.·Genes (Basel)
2025Case report
Loss of function variants in L2HGDH gene causing L-2-hydroxyglutaric aciduria.
Bellad A et al.·Acta Neurol Belg
2023Case report
[Analysis of L2HGDH gene mutation in a patient with 2-hydroxyglutaric aciduria].
Deng Y et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2016
Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria.
Peng W et al.·BMC Med Genet
2018Case report
Clinical, neuroimaging, and genetic features of L-2-hydroxyglutaric aciduria in Arab kindreds.
Faiyaz-Ul-Haque M et al.·Ann Saudi Med
2014
A novel compound heterozygous mutation of the L2HGDH gene in a Chinese boy with L-2-hydroxyglutaric aciduria: case report and literature review.
Zhang Y et al.·Neurol Sci
2018Review
Non-Susceptibility Gene Variants in Head and Neck Paragangliomas.
Snezhkina AV et al.·Int J Mol Sci
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools