HMGCL

Chr 1AR

3-hydroxy-3-methylglutaryl-CoA lyase

Also known as: HL, HMGCL1

NCBI Gene: 3155 ENSG00000117305 UniProt: P35914 OMIM: 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene belongs to the HMG-CoA lyase family. It is a mitochondrial enzyme that catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Mutations in this gene are associated with HMG-CoA lyase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

OMIM ResearchGenerating clinical summary…

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

120 unique Pathogenic / Likely Pathogenic· 151 VUS of 584 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 OE?0.67 (0.42–1.11)

0≤0.351.4

Missense OE?0.90 (0.79–1.03)

0≤0.61.4

Synonymous OE?1.02

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

This gene — mechanism propensity

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

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

584 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51

Likely Pathogenic69

VUS151

Likely Benign276

Benign18

Conflicting13

Pathogenic

Likely Pathogenic

151

VUS

276

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	32	4	15	0	51
Likely Pathogenic	52	14	3	0	69
VUS	4	124	17	6	151
Likely Benign	0	3	133	140	276
Benign	0	0	15	3	18
Conflicting	—				13
Total	88	145	183	149	578

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap HMGCL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →