HMGCL

Chr 1AR

3-hydroxy-3-methylglutaryl-CoA lyase

Also known as: HL, HMGCL1

NCBI Gene: 3155ENSG00000117305UniProt: P35914OMIM: 613898

The encoded mitochondrial enzyme catalyzes the final step of leucine degradation and is essential for ketone body formation. Mutations cause HMG-CoA lyase deficiency, an autosomal recessive disorder characterized by episodes of metabolic acidosis, hypoglycemia, and hyperammonemia, typically triggered by fasting or illness. The pathogenic mechanism involves loss of enzyme function leading to impaired ketogenesis and toxic accumulation of leucine metabolites.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismARLOEUF 1.111 OMIM phenotype
Clinical Summary— HMGCL
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Gene-Disease Validity (ClinGen)
3-hydroxy-3-methylglutaric aciduria · 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
96 unique Pathogenic / Likely Pathogenic· 134 VUS of 500 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.11LOEUF
pLI 0.000
Z-score 1.23
OE 0.67 (0.42–1.11)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.46Z-score
OE missense 0.90 (0.79–1.03)
157 obs / 174.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.67 (0.42–1.11)
0≤0.351.4
Missense OE0.90 (0.79–1.03)
0≤0.61.4
Synonymous OE1.02
0≤1.21.6
LoF obs/exp: 11 / 16.4Missense obs/exp: 157 / 174.1Syn Z: -0.13
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveHMGCL-related 3-hydroxy-3-methylglutaryl-CoA lyase deficiencyLOFAR

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

DN
0.82top 10%
GOF
0.4875th %ile
LOF
0.3162th %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

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic52
VUS134
Likely Benign247
Benign11
Conflicting6
44
Pathogenic
52
Likely Pathogenic
134
VUS
247
Likely Benign
11
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
2
17
0
44
Likely Pathogenic
40
9
3
0
52
VUS
1
111
16
6
134
Likely Benign
0
2
121
124
247
Benign
0
0
11
0
11
Conflicting
—6
Total66124168130494

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

View in ClinVar →

Protein Context — Lollipop Plot

HMGCL · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
HMGCL activates autophagy in osteosarcoma through beta-HB mediated inhibition of the PI3K/AKT/mTOR signaling pathway
Liu W et al.·J Transl Med
2025
Identification of potential biomarkers associated with mitochondrial oxidative stress in idiopathic pulmonary arterial hypertension via bioinformatic and experimental analysis
Zhu Y et al.·Sci Rep
2025
HMGCL-induced beta-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility
Cui X et al.·Hepatol Int
2022
Identification of biomarkers associated with M1 macrophages in the ST-segment elevation myocardial infarction through bioinformatics and machine learning approaches
Li H et al.·Sci Rep
2025
Metabolic Modulation of Histone Acetylation Mediated by HMGCL Activates the FOXM1/beta-catenin Pathway in Glioblastoma.
Sun Y et al.·Neuro Oncol
2023
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Treatment of HMG-CoA Lyase Deficiency-Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases.
Thompson S et al.·Nutrients
2023Review
Integrated multi-omics insight into the molecular networks of oxidative stress in triggering multiple sclerosis.
Xu Y et al.·Neurobiol Dis
2025
Novel FUCA1 variants in two families, including the first report of a contiguous gene deletion syndrome involving FUCA1 and HMGCL.
Kılıç M et al.·Turk J Pediatr
2025Case report
3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: case report of a child with rare HMGCL gene variants.
Bjelica M et al.·J Pediatr Endocrinol Metab
2025Case report
3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients.
Grünert SC et al.·Mol Genet Metab
2017Cohort
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients