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…

LOFmechanismARLOEUF 0.791 OMIM phenotype

Clinical Summary— L2HGDH

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

51 unique Pathogenic / Likely Pathogenic· 147 VUS of 343 total submissions

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveL2HGDH-related L-2-hydroxyglutaric aciduriaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6743th %ile

GOF

0.5661th %ile

LOF

0.3744th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

343 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32

Likely Pathogenic19

VUS147

Likely Benign94

Benign22

Conflicting17

Pathogenic

Likely Pathogenic

147

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	6	8	0	32
Likely Pathogenic	9	9	0	1	19
VUS	3	132	10	2	147
Likely Benign	0	5	36	53	94
Benign	0	1	21	0	22
Conflicting	—				17
Total	30	153	75	56	331

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap L2HGDH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →