HMGCL (3-hydroxy-3-methylglutaryl-CoA lyase)

Gene

• Entrez ID: 3155
• Gene name: 3-hydroxy-3-methylglutaryl-CoA lyase
• Gene symbol: HMGCL
• Synonyms (NCBI Gene): HL, HMGCL1
• Chromosome: 1
• Chromosome location: 1p36.11
• Summary: 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

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs112508527	A>C,G,T	Likely-benign, likely-pathogenic	Synonymous variant, stop gained, coding sequence variant, intron variant
rs121964997	C>T	Pathogenic	Missense variant, coding sequence variant
rs121964998	C>T	Pathogenic	Missense variant, coding sequence variant
rs200189529	G>A,C	Likely-pathogenic, likely-benign	Stop gained, intron variant, coding sequence variant, synonymous variant
rs568718845	T>C	Likely-pathogenic, uncertain-significance	Intron variant
rs727503963	T>C,G	Pathogenic-likely-pathogenic, pathogenic	Coding sequence variant, missense variant
rs752137615	AG>-	Pathogenic, likely-pathogenic	Frameshift variant, coding sequence variant
rs760106433	G>T	Pathogenic, uncertain-significance	Coding sequence variant, missense variant
rs763494292	C>A	Pathogenic	Stop gained, coding sequence variant
rs764264834	GA>-	Pathogenic	Frameshift variant, intron variant, coding sequence variant
rs765198174	G>A,T	Likely-pathogenic, likely-benign	Stop gained, synonymous variant, coding sequence variant
rs770225915	G>A	Likely-pathogenic	Stop gained, coding sequence variant
rs890995574	G>A	Likely-pathogenic	Coding sequence variant, stop gained
rs1184002840	G>-	Likely-pathogenic	Frameshift variant, coding sequence variant
rs1425615804	A>T	Likely-pathogenic	Stop gained, coding sequence variant
rs1553131955	T>C	Likely-pathogenic	Splice acceptor variant
rs1553132209	A>T	Pathogenic	Intron variant, coding sequence variant, missense variant
rs1553132520	T>-	Likely-pathogenic	Intron variant, frameshift variant, coding sequence variant
rs1553133042	->G	Likely-pathogenic	Frameshift variant, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT044352	hsa-miR-106b-5p	CLASH	23622248
MIRT2011329	hsa-miR-1976	CLIP-seq
MIRT2011330	hsa-miR-3160-5p	CLIP-seq
MIRT2011331	hsa-miR-4268	CLIP-seq
MIRT2011332	hsa-miR-4722-3p	CLIP-seq
MIRT2011333	hsa-miR-938	CLIP-seq
MIRT2243541	hsa-miR-4716-5p	CLIP-seq
MIRT2243542	hsa-miR-4749-3p	CLIP-seq
MIRT2243543	hsa-miR-587	CLIP-seq

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000287	Function	Magnesium ion binding	IDA	9200711
GO:0003824	Function	Catalytic activity	IEA
GO:0004419	Function	Hydroxymethylglutaryl-CoA lyase activity	IBA
GO:0004419	Function	Hydroxymethylglutaryl-CoA lyase activity	IDA	8027038, 8670134, 9200711, 9869651, 12464283, 22847177, 22865860
GO:0004419	Function	Hydroxymethylglutaryl-CoA lyase activity	IEA
GO:0005198	Function	Structural molecule activity	IDA	12464283
GO:0005739	Component	Mitochondrion	HTP	34800366
GO:0005739	Component	Mitochondrion	IBA
GO:0005739	Component	Mitochondrion	IDA	9869651
GO:0005739	Component	Mitochondrion	IEA
GO:0005759	Component	Mitochondrial matrix	IEA
GO:0005759	Component	Mitochondrial matrix	NAS	8102917
GO:0005759	Component	Mitochondrial matrix	TAS
GO:0005777	Component	Peroxisome	IDA	9869651, 12464283
GO:0005777	Component	Peroxisome	IEA
GO:0005782	Component	Peroxisomal matrix	TAS
GO:0005829	Component	Cytosol	TAS
GO:0006552	Process	L-leucine catabolic process	IBA
GO:0006552	Process	L-leucine catabolic process	NAS	9200711
GO:0006552	Process	L-leucine catabolic process	TAS	8027038
GO:0006629	Process	Lipid metabolic process	IDA	8027038
GO:0006629	Process	Lipid metabolic process	IEA
GO:0007005	Process	Mitochondrion organization	IEA
GO:0016829	Function	Lyase activity	IEA
GO:0016833	Function	Oxo-acid-lyase activity	IEA
GO:0030145	Function	Manganese ion binding	IDA	9200711
GO:0032991	Component	Protein-containing complex	IDA	12464283
GO:0046872	Function	Metal ion binding	IDA	16330550
GO:0046872	Function	Metal ion binding	IEA
GO:0046951	Process	Ketone body biosynthetic process	IBA
GO:0046951	Process	Ketone body biosynthetic process	IDA	9200711, 22847177, 22865860
GO:0046951	Process	Ketone body biosynthetic process	IEA

Other IDs

• MIM: 613898
• HGNC: 5005
• e!Ensembl: ENSG00000117305

Protein

• UniProt ID: P35914
• Protein name: Hydroxymethylglutaryl-CoA lyase, mitochondrial (HL) (HMG-CoA lyase) (EC 4.1.3.4) (3-hydroxy-3-methylglutarate-CoA lyase)
• Protein 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 (
• PDB: 2CW6, 3MP3, 3MP4, 3MP5
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00682	HMGL-like	32 → 306	HMGL-like	Domain

• Tissue specificity: 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
• Sequence:

  MAAMRKALPRRLVGLASLRAVSTSSMGTLPKRVKIVEVGPRDGLQNEKNIVSTPVKIKLI
  DMLSEAGLSVIETTSFVSPKWVPQMGDHTEVLKGIQKFPGINYPVLTPNLKGFEAAVAAG
  AKEVVIFGAASELFTKKNINCSIEESFQRFDAILKAAQSANISVRGYVSCALGCPYEGKI
  SPAKVAEVTKKFYSMGCYEISLGDTIGVGTPGIMKDMLSAVMQEVPLAALAVHCHDTYGQ
  ALANTLMALQMGVSVVDSSVAGLGGCPYAQGASGNLATEDLVYMLEGLGIHTGVNLQKLL
  EAGNFICQALNRKTSSKVAQATCKL

• Sequence length: 325

Pathways

KEGG:

Valine, leucine and isoleucine degradation
Butanoate metabolism
Metabolic pathways
Peroxisome

Reactome:

Synthesis of Ketone Bodies
Peroxisomal protein import

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession	Evidence Score
Deficiency of hydroxymethylglutaryl-CoA lyase	Likely pathogenic; Pathogenic	rs1638698732, rs1638701269, rs1274176298, rs2148419158, rs778751712, rs2148417048, rs200189529, rs1001955490, rs1322650779, rs2148424154, rs775218067, rs2148424175, rs1638575128, rs2148420687, rs2148419170, rs2148425853, rs1638632303, rs727503963, rs2521455405, rs2521455525, rs763494292, rs2521458985, rs1638447240, rs1259779697, rs2521441733, rs2521380537, rs2521441229, rs2521405619, rs2521455723, rs752137615, rs121964997, rs121964998, rs1357942068, rs2521440674, rs1226874636, rs1638699083, rs765475941, rs1638362423, rs2521475979, rs1467902610, rs2521455305, rs2521404010, rs2521505359, rs766648383, rs2521380983, rs1299646067, rs2521440743, rs2521419194, rs1324641233, rs774211779, rs2521440800, rs786205431, rs568718845, rs760106433, rs764264834, rs1212444447, rs1553132209, rs890995574, rs1553133042, rs1302190999, rs1425615804, rs1184002840, rs1553131955, rs1409716731, rs765198174, rs112508527, rs757884073, rs1553132520, rs770225915, rs779339230, rs1638698938, rs779802353, rs1638575413, rs1638446514, rs1638446662, rs139799938, rs1638619737, rs1638620864	RCV001378372 RCV001377807 RCV001387539 RCV001783422 RCV001783423 RCV001782255 RCV001912675 RCV002025425 RCV002013264 RCV001972669 RCV001977210 RCV001975170 RCV001927048 RCV001870843 RCV001923989 RCV001951304 RCV002250045 RCV000665316 RCV002309942 RCV002307908 RCV000175544 RCV002801151 RCV002819960 RCV002807330 RCV002880465 RCV003006018 RCV003029112 RCV003054546 RCV003059593 RCV003153027 RCV000012732 RCV000012735 RCV000012736 RCV003324314 RCV003476430 RCV003476431 RCV003476432 RCV003476433 RCV003476434 RCV003468355 RCV003476435 RCV003486322 RCV003513581 RCV003513582 RCV003513750 RCV003511630 RCV003512543 RCV003624599 RCV003625453 RCV003625895 RCV003625810 RCV003825024 RCV003837179 RCV003874098 RCV003864699 RCV000032616 RCV000665452 RCV000672903 RCV000672012 RCV000671133 RCV000626227 RCV000672306 RCV000673631 RCV000672347 RCV000670399 RCV000668130 RCV000670074 RCV000672261 RCV000673450 RCV000667662 RCV000673585 RCV000668025 RCV000670504 RCV000672095 RCV000669475 RCV000671577 RCV000778975 RCV001058263 RCV001196408 RCV001215701 RCV001264183 RCV001264184 RCV001264185 RCV001264186 RCV001264187	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
HMGCL-related disorder	Likely pathogenic; Pathogenic	rs727503963, rs779339230	RCV003415999 RCV003411719	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely pathogenic; Pathogenic	rs1638698732, rs1274176298, rs2148419158, rs727503963, rs121964997, rs764264834, rs1212444447, rs1409716731, rs770225915	RCV001831353 RCV001831397 RCV005614676 RCV001831955 RCV001831566 RCV001829746 RCV001829745 RCV001830457 RCV001829857	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Ovarian serous cystadenocarcinoma	Likely pathogenic	rs2521404010	RCV005931499	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
3-HYDROXY-3-METHYLGLUTARIC ACIDURIA	—	GWAS catalog, GenCC	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
AMINO ACID METABOLISM, INBORN ERRORS	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cervical cancer	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hepatocellular carcinoma	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Acute pancreatitis	Pancreatitis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Anemia	Anemia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Anorexia	Anorexia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Cardiomyopathy, Dilated	Cardiomyopathy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Colonic Neoplasms	Colonic neoplasm	Pubtator	34564978	Associate	★☆☆☆☆ Found in Text Mining only
Dysarthria	Dysarthria	HPO_DG			★☆☆☆☆ Found in Text Mining only
Encephalopathies	Epileptic encephalopathy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Glioblastoma	Glioblastoma	Pubtator	38069906	Stimulate	★☆☆☆☆ Found in Text Mining only
Glioma	Glioma	Pubtator	38069906	Associate	★☆☆☆☆ Found in Text Mining only
Hemiplegia, Spastic	Hemiplegia	HPO_DG			★☆☆☆☆ Found in Text Mining only
HEPATIC LIPASE DEFICIENCY (disorder)	HEPATIC LIPASE DEFICIENCY	BEFREE	15308132, 17692550, 19036343, 31721046		★☆☆☆☆ Found in Text Mining only
HMG CoA lyase deficiency	HMG CoA Lyase Deficiency	GENOMICS_ENGLAND_DG	11129331, 24357685, 27604308		★☆☆☆☆ Found in Text Mining only
HMG CoA lyase deficiency	HMG CoA Lyase Deficiency	UNIPROT_DG	11129331, 12746442, 16601870, 17173698, 17459752, 19036343, 19177531, 8798725, 9463337, 9784232		★☆☆☆☆ Found in Text Mining only
HMG CoA lyase deficiency	HMG CoA Lyase Deficiency	CLINVAR_DG	11461194, 14518825, 15308132, 15752612, 16330550, 17173698, 17692550, 19177531, 23465862, 28583327, 8440722, 8798725, 9163320, 9439591, 9463337, 9784232		★☆☆☆☆ Found in Text Mining only
HMG CoA lyase deficiency	HMG CoA Lyase Deficiency	BEFREE	15308132, 17173698, 17692550, 19036343, 19177531, 28583327, 31047871, 31721046		★☆☆☆☆ Found in Text Mining only
HMG CoA lyase deficiency	HMG CoA Lyase Deficiency	CLINGEN_DG	19177531, 20532825, 23861731, 28583327, 3128690, 8440722, 8617516, 9817922		★☆☆☆☆ Found in Text Mining only
HMG CoA lyase deficiency	HMG CoA Lyase Deficiency	ORPHANET_DG	19177531		★☆☆☆☆ Found in Text Mining only
HMG CoA lyase deficiency	HMG CoA Lyase Deficiency	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Hydroxymethylglutaric aciduria	Deficiency of hydroxymethylglutaryl-CoA lyase	ORPHANET_DG	19177531		★☆☆☆☆ Found in Text Mining only
Hydroxymethylglutaric aciduria	Deficiency of hydroxymethylglutaryl-CoA lyase	CLINGEN_DG	19177531, 20532825, 23861731, 28583327, 3128690, 8440722, 8617516, 9817922		★☆☆☆☆ Found in Text Mining only
Hyperuricemia	Hyperuricemia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Hypoglycemia	Hypoglycemia	Pubtator	16330546	Associate	★☆☆☆☆ Found in Text Mining only
Hypoglycemia	Hypoglycemia	BEFREE	25872961		★☆☆☆☆ Found in Text Mining only
Hypoglycemia	Hypoglycemia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Hypoglycemic coma	Hypoglycemic coma	HPO_DG			★☆☆☆☆ Found in Text Mining only
Intellectual Disability	Mental retardation	GENOMICS_ENGLAND_DG	11129331		★☆☆☆☆ Found in Text Mining only
Ketonuria	Ketonuria	HPO_DG			★☆☆☆☆ Found in Text Mining only
Leukemia Hairy Cell	Hairy cell leukemia	Pubtator	26145173	Stimulate	★☆☆☆☆ Found in Text Mining only
Leukoencephalopathy	Leukoencephalopathy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Leukopenia	Leukopenia	HPO_DG			★☆☆☆☆ Found in Text Mining only
melanoma	Melanoma	BEFREE	26145173		★☆☆☆☆ Found in Text Mining only
Melanoma	Melanoma	Pubtator	26145173	Stimulate	★☆☆☆☆ Found in Text Mining only
Metabolic Diseases	Metabolic syndrome	Pubtator	16330546	Associate	★☆☆☆☆ Found in Text Mining only
Microcephaly	Microcephaly	HPO_DG			★☆☆☆☆ Found in Text Mining only
Mild Mental Retardation	Mental retardation	HPO_DG			★☆☆☆☆ Found in Text Mining only
Mitochondrial Diseases	Mitochondrial Diseases	BEFREE	19036343		★☆☆☆☆ Found in Text Mining only
Moderate intellectual disability	Mental retardation	HPO_DG			★☆☆☆☆ Found in Text Mining only
Nasopharyngeal Carcinoma	Nasopharyngeal carcinoma	Pubtator	28931870	Associate	★☆☆☆☆ Found in Text Mining only
Neoplasms	Neoplasms	BEFREE	23082721, 26145173		★☆☆☆☆ Found in Text Mining only
Prostatic Neoplasms	Prostatic neoplasm	Pubtator	23443136	Associate	★☆☆☆☆ Found in Text Mining only
Severe intellectual disability	Mental retardation	HPO_DG			★☆☆☆☆ Found in Text Mining only
Thrombocytosis	Thrombocytosis	HPO_DG			★☆☆☆☆ Found in Text Mining only