HMGCL

Summary

HMGCL (3-hydroxy-3-methylglutaryl-CoA lyase, HGNC:5005) is a protein-coding gene on chromosome 1p36.11, encoding Hydroxymethylglutaryl-CoA lyase, mitochondrial (P35914). Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis.

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.

Source: NCBI Gene 3155 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 3-hydroxy-3-methylglutaric aciduria (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 582 total — 48 pathogenic, 50 likely-pathogenic
• Phenotypes (HPO): 72
• MANE Select transcript: NM_000191

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5005
Approved symbol	HMGCL
Name	3-hydroxy-3-methylglutaryl-CoA lyase
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	HL, HMGCL1
Ensembl gene	ENSG00000117305
Ensembl biotype	protein_coding
OMIM	613898
Entrez	3155

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 30 protein_coding, 5 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000235958, ENST00000374487, ENST00000374490, ENST00000436439, ENST00000479458, ENST00000496907, ENST00000498698, ENST00000509389, ENST00000513148, ENST00000892102, ENST00000892103, ENST00000892104, ENST00000892105, ENST00000892106, ENST00000892107, ENST00000892108, ENST00000892109, ENST00000892110, ENST00000892111, ENST00000892112, ENST00000892113, ENST00000892114, ENST00000892115, ENST00000892116, ENST00000892117, ENST00000892118, ENST00000892119, ENST00000926396, ENST00000926397, ENST00000967920, ENST00000967921, ENST00000967922, ENST00000967923, ENST00000967924, ENST00000967925, ENST00000967926

RefSeq mRNA: 2 — MANE Select: NM_000191 NM_000191, NM_001166059

CCDS: CCDS243, CCDS53279

Canonical transcript exons

ENST00000374490 — 9 exons

Exon	Start	End
ENSE00001463651	23801885	23802564
ENSE00001600452	23825356	23825429
ENSE00003470985	23804400	23804525
ENSE00003491317	23808135	23808323
ENSE00003499235	23810736	23810799
ENSE00003536663	23817476	23817583
ENSE00003637574	23814190	23814338
ENSE00003687914	23820510	23820593
ENSE00003690949	23816675	23816770

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.2288 / max 142.8512, expressed in 1811 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11006	12.4402	1809
11005	0.3997	188
11007	0.3889	158

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.68	gold quality
liver	UBERON:0002107	97.73	gold quality
mucosa of transverse colon	UBERON:0004991	97.04	gold quality
adult mammalian kidney	UBERON:0000082	96.24	gold quality
right adrenal gland	UBERON:0001233	95.93	gold quality
right adrenal gland cortex	UBERON:0035827	95.85	gold quality
cervix squamous epithelium	UBERON:0006922	95.36	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.32	gold quality
left adrenal gland	UBERON:0001234	95.15	gold quality
nephron tubule	UBERON:0001231	95.06	gold quality
rectum	UBERON:0001052	94.99	gold quality
left adrenal gland cortex	UBERON:0035825	94.92	gold quality
adrenal cortex	UBERON:0001235	94.67	gold quality
kidney	UBERON:0002113	94.54	gold quality
adrenal gland	UBERON:0002369	94.37	gold quality
kidney epithelium	UBERON:0004819	94.25	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.22	gold quality
type B pancreatic cell	CL:0000169	93.96	silver quality
transverse colon	UBERON:0001157	93.77	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.75	gold quality
cortex of kidney	UBERON:0001225	93.65	gold quality
apex of heart	UBERON:0002098	93.54	gold quality
metanephros cortex	UBERON:0010533	93.53	gold quality
ileal mucosa	UBERON:0000331	93.50	gold quality
duodenum	UBERON:0002114	93.28	gold quality
biceps brachii	UBERON:0001507	93.24	gold quality
adrenal tissue	UBERON:0018303	93.22	gold quality
colonic mucosa	UBERON:0000317	93.07	gold quality
body of stomach	UBERON:0001161	93.05	gold quality
right uterine tube	UBERON:0001302	92.94	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7606	no	315.21
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting HMGCL, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4727-5P	99.23	67.55	1154
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-11399	98.71	65.69	869
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-6817-5P	97.95	67.86	1026
HSA-MIR-15B-3P	97.85	66.68	974
HSA-MIR-483-3P	97.77	64.95	731
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-6729-3P	96.91	66.79	703
HSA-MIR-4732-5P	90.07	64.77	412

Literature-anchored findings (GeneRIF, showing 23)

• The peroxisomal enzyme forms a covalently linked dimeric species upon crosslinking with dibromopropanone or o-phenylenedimaleimide . Cysteine-323 is required for intersubunit covalent crosslinking. (PMID:12464283)
• A role is suggested for arginine-41 in deprotonation or enolization of acetyldithio-CoA, implicating this residue in the HMG-CoA cleavage reaction chemistry that leads to acetyl-CoA product formation. (PMID:15122894)
• Data describe the DNA mutational analysis of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. (PMID:15164951)
• Exon 2 of HL skipping led to the loss of beta-sheet 1, and the skipping of exons 2 and 3 caused the disappearance of alpha helix 1 and beta-sheets 1 and 2 (PMID:15752612)
• Crystal structure of human 3-hydroxy-3-methylglutaryl-CoA Lyase (PMID:16330550)
• findings of common mutations in HMGCL have direct implications on rapid molecular diagnosis, prenatal and pre-implantation diagnosis and population based prevention programs directed towards 3HMG in Saudi Arabia. (PMID:17173698)
• HMG-CoA located on the surface of the enzyme implicates Asn(311) and Lys(313) in substrate binding by establishing polar contacts with phosphate and ribose groups of adenosine, and Lys(48) by contacting the carboxyl group of the panthotenic acid moiety. (PMID:17459752)
• The unique HMGCL gene mutations exist in Taiwanese 3-hydroxy-3-methylglutaryl CoA lyase deficiency deficiency patients. (PMID:19036343)
• Finding that all identified missense mutations cause a >95% decrease in the enzyme activity, indicates that the disease appears only in very severe genotypes. (PMID:19177531)
• We report on a new case of 3-hydroxy-3-methylglutaric aciduria particular by its late onset in a 3-year-old patient. Molecular investigation identified two new sequence modifications in the HMGCL gene: c.494G>A (p.Arg165Gln) and c.820G>A (p.Gly274Arg). (PMID:19932602)
• Crystal structures of ternary complexes of WT HMGCL with the competitive inhibitor 3-hydroxyglutaryl-CoA and of the catalytically deficient HMGCL R41M mutant with substrate HMG-CoA have been determined to 2.4 and 2.2 A. (PMID:20558737)
• levels of enzyme activity do not strongly correlate with formation of inter-subunit adducts by HMGCL mutants. C170S, C266S, and C323S proteins do not form inter-subunit disulfide adducts but such an adduct is restored in the C170S/C174S double mutant. (PMID:21514269)
• An alternative transcript of HMGCS2 carrying a deletion of exon 4, and two alternative transcripts of HMGCL with deletions of exons 5 and 6, and exons 5, 6 and 7, respectively, were detected. (PMID:21952825)
• analysis of HMGCLL1 as an extramitochondrial human 3-hydroxy-3-methylglutaryl-CoA lyase and comparison with MHGCL (PMID:22865860)
• in the 2 stop codon mutations c.109G>T and c.504_505delCT studied, the stop codon does not appear to be the cause of aberrant splicing; the mutation c.504_505delCT causes 2 mRNA transcripts with a stop codon that generate two simultaneous nonsense-mediated mRNA decay phenomena (PMID:23465862)
• This efficient UPLC-MS/MS assay permits rapid and high sensitive determination of HMGCR enzyme activity, tracing potential alterations in cholesterol biosynthesis. (PMID:24333427)
• The genetic analysis revealed a novel homozygote deletion in exon 3 and 4 in HMGCL gene. HMG-CoA lyase deficiency should be thought in the patients with hypoketotic hypoglycemia, hyperammonemia, elevated liver function tests, noncompaction left ventricle and characteristic white matter changes and in the differential diagnosis of macrocephaly. (PMID:25708061)
• this is the first study describing HMGCL deficiency caused by uniparental disomy. (PMID:25872961)
• Data suggest that HMGCS1 (HMG-CoA synthase 1) signals through ketogenesis/acetoacetate to promote cell proliferation and BRAF(V600E)-dependent MEK1 activation in BRAF(V600E)-positive melanoma and colon cancer cells; HMGCS1 co-localizes with HMGCL (HMG-CoA lyase) and BRAF(V600E) in cytosol of melanoma and colon cancer cells. (BRAF = proto-oncogene protein B-raf) (PMID:28468827)
• The expression of HMGCL was silenced in nasopharyngeal carcinoma tissue. Downregulation of HMGCL in nasopharyngeal carcinoma was associated with low intracellular beta-hydroxybutyrate (beta-HB) production, thereby reducing reactive oxygen species (ROS) generation. (PMID:28931870)
• HMGCL-induced beta-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility. (PMID:36508088)
• Metabolic modulation of histone acetylation mediated by HMGCL activates the FOXM1/beta-catenin pathway in glioblastoma. (PMID:38069906)
• miR-1202 regulates BPH-1 cell proliferation, apoptosis, and epithelial-to-mesenchymal transition through targeting HMGCL. (PMID:38551020)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmgcl	ENSDARG00000021220
mus_musculus	Hmgcl	ENSMUSG00000028672
rattus_norvegicus	Hmgcl	ENSRNOG00000009422
drosophila_melanogaster	Hmgcl	FBGN0031877
caenorhabditis_elegans	Y71G12B.10	WBGENE00022150

Paralogs (1): HMGCLL1 (ENSG00000146151)

Protein

Protein identifiers

Hydroxymethylglutaryl-CoA lyase, mitochondrial — P35914 (reviewed: P35914)

Alternative names: 3-hydroxy-3-methylglutarate-CoA lyase

All UniProt accessions (2): P35914, H0Y2L7

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis. Terminal step in leucine catabolism. Ketone bodies (beta-hydroxybutyrate, acetoacetate and acetone) are essential as an alternative source of energy to glucose, as lipid precursors and as regulators of metabolism.

Subunit / interactions. Homodimer; disulfide-linked. Can also form homotetramers.

Subcellular location. Mitochondrion matrix. Peroxisome.

Tissue specificity. Highest expression in liver. Expressed in pancreas, kidney, intestine, testis, fibroblasts and lymphoblasts. Very low expression in brain and skeletal muscle. The relative expression of isoform 2 (at mRNA level) is highest in heart (30%), skeletal muscle (22%), and brain (14%).

Disease relevance. 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) [MIM:246450] An autosomal recessive disease affecting ketogenesis and L-leucine catabolism. The disease usually appears in the first year of life after a fasting period and its clinical acute symptoms include vomiting, seizures, metabolic acidosis, hypoketotic hypoglycemia and lethargy. These symptoms sometimes progress to coma, with fatal outcome in some cases. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Stimulated by reducing agents such as dithiothreitol (DTT).

Pathway. Metabolic intermediate metabolism; (S)-3-hydroxy-3-methylglutaryl-CoA degradation; acetoacetate from (S)-3-hydroxy-3-methylglutaryl-CoA: step 1/1.

Miscellaneous. The transcript is not translated, but would result in a catalytically impaired product if it was. Very low expression. The transcript is not translated, but would result in a catalytically inactive product if it was.

Similarity. Belongs to the HMG-CoA lyase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P35914-1	1	yes
P35914-2	2, HMGCS2delta5,6
P35914-3	3, HMGCS2delta5,6,7

RefSeq proteins (2): NP_000182, NP_001159531 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000138	HMG_CoA_lyase_AS	Active_site
IPR000891	PYR_CT	Domain
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR043594	HMGL	Family

Pfam: PF00682

Enzyme classification (BRENDA):

• EC 4.1.3.4 — hydroxymethylglutaryl-CoA lyase (BRENDA: 18 organisms, 13 substrates, 23 inhibitors, 22 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(S)-3-HYDROXY-3-METHYLGLUTARYL-COA	0.02–62	11
HYDROXYMETHYLGLUTARYL-COA	0.008–0.053	7
3-HYDROXY-3-METHYLGLUTARYL-COA	0.0134–0.0265	4

Catalyzed reactions (Rhea), 1 shown:

• (3S)-3-hydroxy-3-methylglutaryl-CoA = acetoacetate + acetyl-CoA (RHEA:24404)

UniProt features (76 total): sequence variant 19, helix 14, mutagenesis site 10, modified residue 8, strand 7, binding site 5, turn 4, splice variant 2, transit peptide 1, chain 1, disulfide bond 1, domain 1, short sequence motif 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2CW6	X-RAY DIFFRACTION	2.1
3MP4	X-RAY DIFFRACTION	2.2
3MP5	X-RAY DIFFRACTION	2.25
3MP3	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35914-F1	92.11	0.87

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 266

Ligand- & substrate-binding residues (5): 41; 42; 233; 235; 275

Post-translational modifications (8): 48, 48, 111, 137, 137, 179, 179, 324

Disulfide bonds (1): 323

Mutagenesis-validated functional residues (10):

Position	Phenotype
37	normal activity.
41	reduced activity, and loss of proton exchange.
42	loss of activity, and reduced proton exchange rate.
72	loss of activity, and reduced affinity for metal cofactor and substrate.
204	reduced activity, and reduced affinity for metal cofactor and substrate.
233	loss of activity, and reduced proton exchange rate.
266	loss of activity.
279	reduced thermal stability, but normal activity.
280	normal activity.
323	abolishes interchain homodimerization. exhibits no dtt stimulated activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-77111	Synthesis of Ketone Bodies
R-HSA-9033241	Peroxisomal protein import

MSigDB gene sets: 306 (showing top): YANG_BREAST_CANCER_ESR1_LASER_UP, GNF2_GSTM1, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, RIZKI_TUMOR_INVASIVENESS_3D_DN, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GNF2_LCAT, HSIAO_LIVER_SPECIFIC_GENES, GOBP_LIPID_METABOLIC_PROCESS, GNF2_HPX

GO Biological Process (4): L-leucine catabolic process (GO:0006552), lipid metabolic process (GO:0006629), mitochondrion organization (GO:0007005), ketone body biosynthetic process (GO:0046951)

GO Molecular Function (8): magnesium ion binding (GO:0000287), hydroxymethylglutaryl-CoA lyase activity (GO:0004419), structural molecule activity (GO:0005198), manganese ion binding (GO:0030145), metal ion binding (GO:0046872), catalytic activity (GO:0003824), lyase activity (GO:0016829), oxo-acid-lyase activity (GO:0016833)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), peroxisome (GO:0005777), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ketone body metabolism	1
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
molecular_function	2
cytoplasm	2
L-leucine metabolic process	1
branched-chain amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
primary metabolic process	1
organelle organization	1
small molecule biosynthetic process	1
fatty acid derivative biosynthetic process	1
metal ion binding	1
oxo-acid-lyase activity	1
transition metal ion binding	1
cation binding	1
catalytic activity	1
carbon-carbon lyase activity	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
microbody	1
peroxisome	1
microbody lumen	1
cellular anatomical structure	1
cellular_component	1

Protein interactions and networks

STRING

2323 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMGCL	HMGCS2	P54868	788
HMGCL	BDH1	Q02338	745
HMGCL	OXCT1	P55809	732
HMGCL	HMGCS1	Q01581	720
HMGCL	ACO2	Q99798	705
HMGCL	ACO1	P21399	700
HMGCL	NDUFA1	O15239	684
HMGCL	ACAT1	P24752	662
HMGCL	OXCT2	Q9BYC2	637
HMGCL	AUH	Q13825	628
HMGCL	SOD2	P04179	607
HMGCL	F5H3C5	F5H3C5	601
HMGCL	ACAA2	P42765	579
HMGCL	HADHB	P55084	577
HMGCL	MCCC2	Q9HCC0	568

IntAct

26 interactions, top by confidence:

A	B	Type	Score
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
PBK	TRIM37	psi-mi:“MI:0914”(association)	0.550
CTDSP1	CTDSP2	psi-mi:“MI:0914”(association)	0.530
HMGCL	DBT	psi-mi:“MI:0914”(association)	0.530
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
GTF2B	HMGCL	psi-mi:“MI:0915”(physical association)	0.370
ADAMTS10	HMGCL	psi-mi:“MI:0915”(physical association)	0.370
ARL6IP1	HMGCL	psi-mi:“MI:0915”(physical association)	0.370
HMGCL	DNAJA1	psi-mi:“MI:0915”(physical association)	0.370
HMGCL	HES1	psi-mi:“MI:0915”(physical association)	0.370
RNF126	HMGCL	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
NTAQ1	SBNO1	psi-mi:“MI:0914”(association)	0.350
HMGCL	GLS	psi-mi:“MI:0914”(association)	0.350
HMGCLL1	LSP1	psi-mi:“MI:0914”(association)	0.350
HMGCLL1	ADAMTS4	psi-mi:“MI:0914”(association)	0.350
PCCB	SCGB2A1	psi-mi:“MI:0914”(association)	0.350
COMMD2		psi-mi:“MI:0914”(association)	0.350
HMGCL	PDHX	psi-mi:“MI:0914”(association)	0.350
TRMT61B	PRORP	psi-mi:“MI:0914”(association)	0.350
CAT	VWA8	psi-mi:“MI:2364”(proximity)	0.270
HMGCL		psi-mi:“MI:0915”(physical association)	0.000
MS4A7	HMGCL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (91): PNPT1 (Affinity Capture-MS), FPGS (Affinity Capture-MS), GLS (Affinity Capture-MS), ALAS1 (Affinity Capture-MS), ACADVL (Affinity Capture-MS), MGME1 (Affinity Capture-MS), FBXO21 (Affinity Capture-MS), HMGCL (Co-fractionation), HMGCL (Co-fractionation), LSM12 (Co-fractionation), TOMM40 (Co-fractionation), HMGCL (Two-hybrid), FPGS (Affinity Capture-MS), HMGCL (Affinity Capture-MS), HMGCL (Affinity Capture-MS)

ESM2 similar proteins: A0JME6, A6QLY4, B5X0W9, F6HDM2, G4YEI5, O49472, P08030, P09556, P13995, P35914, P47956, P47957, P54886, P54889, P85094, Q01637, Q08C33, Q0P5C2, Q32KX0, Q32LQ3, Q3T099, Q43153, Q4R826, Q54NZ6, Q54NZ8, Q5M8W9, Q5PQ71, Q5R4M8, Q5R9E1, Q5RC03, Q5U3Z3, Q5ZKA5, Q68FS1, Q6DF67, Q6I7R3, Q6NY77, Q8HXZ6, Q8K009, Q8LG77, Q8TB37

Diamond homologs: A3NML2, A3P825, A5UWE6, A7NLU2, A8WG57, A9WGE2, D4A5C3, O34873, O81027, P13703, P35914, P35915, P38060, P97519, Q0PHX9, Q29448, Q2T7S9, Q3ACM0, Q3JK55, Q5R9E1, Q63JB1, Q8HXZ6, Q8JZS7, Q8TB92, Q9I2A0, A0PR18, A7IDU6, A8GG86, B1VRH5, B2HGH1, B8ESV2, Q5NXN2, Q6D796, Q99PZ1, Q9X9Q0, A1AWA1, A5CWZ3, P54610, Q2RHL3, Q47884

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

582 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	48
Likely pathogenic	50
Uncertain significance	151
Likely benign	271
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074299	NM_000191.3(HMGCL):c.308_317dup (p.Thr107fs)	Pathogenic
11954	NM_000191.3(HMGCL):c.206_207del (p.Ser69fs)	Pathogenic
11956	NG_013061.1:g.(9952_12876)_(19725_22136)del	Pathogenic
11957	NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)	Pathogenic
1323059	NM_000191.3(HMGCL):c.71C>A (p.Ser24Ter)	Pathogenic
1324535	NM_000191.3(HMGCL):c.769del (p.Asp257fs)	Pathogenic
1369836	NM_000191.3(HMGCL):c.545del (p.Pro182fs)	Pathogenic
1410691	NC_000001.10:g.(?24137216)(24151915_?)del	Pathogenic
1425974	NM_000191.3(HMGCL):c.392del (p.Ala130_Ser131insTer)	Pathogenic
1457586	NM_000191.3(HMGCL):c.242G>A (p.Trp81Ter)	Pathogenic
1458760	NC_000001.10:g.(?24140670)(24140838_?)del	Pathogenic
1459181	NM_000191.3(HMGCL):c.208_209del (p.Val70fs)	Pathogenic
1459698	NC_000001.10:g.(?24128943)(24131025_?)del	Pathogenic
1459880	NM_000191.3(HMGCL):c.133C>T (p.Gln45Ter)	Pathogenic
195033	NM_000191.3(HMGCL):c.109G>T (p.Glu37Ter)	Pathogenic
1993106	NM_000191.3(HMGCL):c.250C>T (p.Gln84Ter)	Pathogenic
1997196	NM_000191.3(HMGCL):c.178_187del (p.Ile60fs)	Pathogenic
1999926	NM_000191.3(HMGCL):c.690_698del (p.Ala231_His233del)	Pathogenic
2096036	NM_000191.3(HMGCL):c.874_876+31del	Pathogenic
2107245	NM_000191.3(HMGCL):c.394_406dup (p.Lys136fs)	Pathogenic
2422558	NC_000001.10:g.(?24128943)(24129064_?)del	Pathogenic
2422559	NC_000001.10:g.(?24146990)(24151915_?)del	Pathogenic
2444229	NM_000191.3(HMGCL):c.253-2A>G	Pathogenic
2676030	NM_000191.3(HMGCL):c.497+1dup	Pathogenic
2733863	NM_000191.3(HMGCL):c.144G>T (p.Lys48Asn)	Pathogenic
2738582	NM_000191.3(HMGCL):c.319del (p.Thr107fs)	Pathogenic
2827065	NM_000191.3(HMGCL):c.874dup (p.Thr292fs)	Pathogenic
2848766	NM_000191.3(HMGCL):c.484dup (p.Ile162fs)	Pathogenic
3016011	NM_000191.3(HMGCL):c.724_725del (p.Leu242fs)	Pathogenic
3247674	NC_000001.10:g.(?24151826)(24151905_?)del	Pathogenic

SpliceAI

1408 predictions. Top by Δscore:

Variant	Effect	Δscore
1:23810795:CGTAC:C	acceptor_gain	1.0000
1:23810799:CCTGT:C	acceptor_loss	1.0000
1:23810800:CTGTG:C	acceptor_loss	1.0000
1:23810801:T:G	acceptor_loss	1.0000
1:23816673:A:AC	donor_gain	1.0000
1:23816674:C:CC	donor_gain	1.0000
1:23816674:CCG:C	donor_gain	1.0000
1:23816766:CCCAT:C	acceptor_gain	1.0000
1:23816767:CCAT:C	acceptor_gain	1.0000
1:23816767:CCATC:C	acceptor_gain	1.0000
1:23816768:CAT:C	acceptor_gain	1.0000
1:23816768:CATC:C	acceptor_gain	1.0000
1:23816771:C:CC	acceptor_gain	1.0000
1:23816779:C:CT	acceptor_gain	1.0000
1:23817470:GCTCA:G	donor_loss	1.0000
1:23817471:CTCA:C	donor_loss	1.0000
1:23817472:TCA:T	donor_loss	1.0000
1:23817473:CACC:C	donor_loss	1.0000
1:23817474:ACC:A	donor_loss	1.0000
1:23817475:C:T	donor_loss	1.0000
1:23817580:TATT:T	acceptor_gain	1.0000
1:23817582:TT:T	acceptor_gain	1.0000
1:23817584:C:CC	acceptor_gain	1.0000
1:23817589:G:GC	acceptor_gain	1.0000
1:23820601:T:C	acceptor_gain	1.0000
1:23820601:T:TC	acceptor_gain	1.0000
1:23825354:A:AC	donor_gain	1.0000
1:23825354:ACAG:A	donor_gain	1.0000
1:23825354:ACAGC:A	donor_gain	1.0000
1:23825355:C:CC	donor_gain	1.0000

AlphaMissense

2093 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:23817503:G:C	S75R	0.995
1:23817503:G:T	S75R	0.995
1:23817505:T:G	S75R	0.995
1:23808275:C:G	D204H	0.988
1:23804434:A:G	L281P	0.986
1:23808265:C:T	G207D	0.984
1:23817560:T:A	K56N	0.983
1:23817560:T:G	K56N	0.983
1:23820532:C:G	R41P	0.983
1:23804451:G:C	N275K	0.982
1:23804451:G:T	N275K	0.982
1:23808139:A:G	L249P	0.982
1:23814285:G:C	F134L	0.982
1:23814285:G:T	F134L	0.982
1:23814287:A:G	F134L	0.982
1:23816677:C:G	A116P	0.982
1:23817500:A:C	F76L	0.982
1:23817500:A:T	F76L	0.982
1:23817502:A:G	F76L	0.982
1:23817540:A:G	L63P	0.981
1:23817552:A:G	L59P	0.981
1:23804480:A:G	C266R	0.980
1:23808190:A:T	V232D	0.980
1:23820523:A:G	L44P	0.980
1:23808274:T:A	D204V	0.979
1:23820519:T:A	Q45H	0.979
1:23820519:T:G	Q45H	0.979
1:23808274:T:G	D204A	0.978
1:23804495:C:G	A261P	0.977
1:23808265:C:A	G207V	0.977

dbSNP variants (sampled 300 via entrez): RS1000065020 (1:23825992 G>A), RS1000380428 (1:23823478 G>A,C,T), RS1000477445 (1:23804066 T>G), RS1000664502 (1:23824689 T>C,G), RS1000730550 (1:23823207 T>A,C), RS1000815654 (1:23818556 ATT>A,AT,ATTT), RS1001001283 (1:23817345 C>G), RS1001120627 (1:23824967 A>T), RS1001194680 (1:23801490 A>T), RS1001284344 (1:23823378 C>T), RS1001344181 (1:23821848 GCTT>G), RS1001487434 (1:23815473 A>C), RS1001596104 (1:23814368 C>G,T), RS1001609984 (1:23827138 A>G), RS1001795152 (1:23822064 C>T)

Disease associations

OMIM: gene MIM:613898 | disease phenotypes: MIM:246450, MIM:609016

GenCC curated gene-disease

Disease	Classification	Inheritance
3-hydroxy-3-methylglutaric aciduria	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
3-hydroxy-3-methylglutaric aciduria	Definitive	AR

Mondo (2): 3-hydroxy-3-methylglutaric aciduria (MONDO:0009520), long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (MONDO:0012173)

Orphanet (2): 3-hydroxy-3-methylglutaric aciduria (Orphanet:20), Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Orphanet:5)

HPO phenotypes

72 total (30 of 72 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000741	Apathy
HP:0000952	Jaundice
HP:0000969	Edema
HP:0000980	Pallor
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001259	Coma
HP:0001260	Dysarthria
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001298	Encephalopathy
HP:0001325	Hypoglycemic coma
HP:0001336	Myoclonus
HP:0001644	Dilated cardiomyopathy
HP:0001695	Cardiac arrest
HP:0001735	Acute pancreatitis
HP:0001824	Weight loss
HP:0001882	Decreased total leukocyte count
HP:0001894	Thrombocytosis
HP:0001903	Anemia
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001944	Dehydration

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004611_105	High light scatter reticulocyte count	1.000000e-12
GCST004619_35	Reticulocyte fraction of red cells	3.000000e-11
GCST004628_5	Immature fraction of reticulocytes	8.000000e-12
GCST90002403_38	Red blood cell count	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538324	3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, increases expression	3
Acetaminophen	increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Valproic Acid	affects cotreatment, increases expression, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
afuresertib	increases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
dinophysistoxin 1	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression	1
Atrazine	increases expression	1
Cadmium	increases abundance, increases expression	1
Cisplatin	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1

Clinical trials (associated diseases)

7 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT01494051	PHASE1/PHASE2	COMPLETED	High Protein Diet in Patients With Long-chain Fatty Acid Oxidation Disorders
NCT05411835	EARLY_PHASE1	COMPLETED	Oral Ketones and Exercise Among Patients With Long-chain Fatty Acid Oxidation Disorders
NCT02517307	Not specified	COMPLETED	Fatty Acid Oxidation Defects and Insulin Sensitivity
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening