LIAS

Chr 4AR

lipoic acid synthetase

Also known as: HGCLAS, HUSSY-01, LAS, LIP1, LS, PDHLD

NCBI Gene: 11019 ENSG00000121897 UniProt: O43766 OMIM: 607031

This mitochondrial iron-sulfur enzyme catalyzes the final step in lipoic acid biosynthesis, a potent antioxidant essential for cellular metabolism. Mutations cause autosomal recessive hyperglycinemia, lactic acidosis, and seizures through loss of function. The condition presents with neonatal-onset epilepsy and metabolic derangements due to deficient lipoic acid synthesis.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene belongs to the biotin and lipoic acid synthetases family. Localized in the mitochondrion, this iron-sulfur enzyme catalyzes the final step in the de novo pathway for the biosynthesis of lipoic acid, a potent antioxidant. The deficient expression of this enzyme has been linked to conditions such as diabetes, atherosclerosis and neonatal-onset epilepsy. Alternative splicing occurs at this locus, and several transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Aug 2020]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.841 OMIM phenotype

Clinical Summary— LIAS

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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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

33 unique Pathogenic / Likely Pathogenic· 191 VUS of 463 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — LIAS

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?

0.84LOEUF

pLI 0.000

Z-score 2.11

OE 0.51 (0.32–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.25Z-score

OE missense 0.75 (0.66–0.86)

153 obs / 203.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.32–0.84)

0≤0.351.4

Missense OE?0.75 (0.66–0.86)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 11 / 21.6Missense obs/exp: 153 / 203.3Syn Z: 0.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongLIAS-related neonatal-onset epilepsy, defective mitochondrial energy metabolism and glycine elevationOTHERAR

This gene — mechanism propensity

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

0.75top 25%

GOF

0.4974th %ile

LOF

0.3648th %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

463 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic13

VUS191

Likely Benign173

Benign45

Conflicting13

Pathogenic

Likely Pathogenic

191

VUS

173

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	1	0	0	20
Likely Pathogenic	10	3	0	0	13
VUS	3	171	15	2	191
Likely Benign	0	12	95	66	173
Benign	0	1	42	2	45
Conflicting	—				13
Total	32	188	152	70	455

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap LIAS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →