L2HGDH

Chr 14AR

L-2-hydroxyglutarate dehydrogenase

Also known as: C14orf160, L2HGA

NCBI Gene: 79944 ENSG00000087299 UniProt: Q9H9P8 OMIM: 609584

L-2-hydroxyglutarate dehydrogenase is a FAD-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in mammalian tissues. Mutations cause L-2-hydroxyglutaric aciduria, an autosomal recessive neurometabolic disorder resulting in moderate to severe cognitive disability. The gene is highly constrained against loss-of-function variants (pLI near 0, LOEUF 0.787), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

L-2-hydroxyglutaric aciduriaMIM #236792

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mitochondrial disease · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.79

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — L2HGDH

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.000

Z-score 2.34

OE 0.48 (0.30–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.42Z-score

OE missense 0.93 (0.83–1.03)

235 obs / 254.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.30–0.79)

0≤0.351.4

Missense OE?0.93 (0.83–1.03)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 11 / 23.1Missense obs/exp: 235 / 254.0Syn Z: 0.70

Background carrier burden — how many people carry a rare variant somewhere in L2HGDH?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 77

686 rare PASS variants

Rare truncating (LoF)

1 in 1,800

107 rare PASS variants

Rare synonymous (reference)

1 in 250

240 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for L2HGDH. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 2,100
South Asian	~43k	1 in 83	1 in 4,100
Remaining (unassigned)	~30k	1 in 61	1 in 660
European (Finnish)	~27k	1 in 430	≈ 1 in 8,700
Admixed American	~22k	1 in 82	1 in 1,100
African / African American	~21k	1 in 71	1 in 1,800
East Asian	~20k	1 in 120	1 in 510
Ashkenazi Jewish	~13k	1 in 1,800	none seen
Middle Eastern	~2,884	1 in 77	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 10 coding exons well covered in gnomAD exomes; exon 6 marginal. Genomes: all 10.? see exons ↓