HMGCL

3-hydroxy-3-methylglutaryl-CoA lyase

Basic information

Region (hg38): 1:23801885-23838620

Links

ENSG00000117305 ∙ NCBI:3155 ∙ OMIM:613898 ∙ HGNC:5005 ∙ Uniprot:P35914 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 3-hydroxy-3-methylglutaric aciduria (Definitive), mode of inheritance: AR
• 3-hydroxy-3-methylglutaric aciduria (Definitive), mode of inheritance: AR
• 3-hydroxy-3-methylglutaric aciduria (Strong), mode of inheritance: AR
• 3-hydroxy-3-methylglutaric aciduria (Strong), mode of inheritance: AR
• 3-hydroxy-3-methylglutaric aciduria (Supportive), mode of inheritance: AR
• 3-hydroxy-3-methylglutaric aciduria (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
3-hydroxy-3-methylglutaryl-CoA lyase deficiency	AR	Biochemical	Treatment to prevent and efficiently treat metabolic decompenstation can be beneficial; Avoidance of prolonged fasting and chronic low-fat, protein (including leucine)-restricted diet with carnitine supplementation can be beneficial	Biochemical; Neurologic	1256504; 1000856; 91680; 85928; 6156427; 6112838; 6489380; 6475954; 3099065; 3128690; 2246860; 8440722; 8617516; 11129331; 17692550; 19177531; 19932602

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HMGCL gene.

• Deficiency of hydroxymethylglutaryl-CoA lyase (33 variants)
• Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (5 variants)
• not provided (4 variants)
• Inborn genetic diseases (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HMGCL gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				130	3	133
missense	4	6	93	2		105
nonsense	6	14	1			21
start loss		1	1			2
frameshift	18	11				29
inframe indel	1		3			4
splice donor/acceptor (+/-2bp)	4	16				20
splice region			10	30		40
non coding			7	93	7	107
Total	33	48	105	225	10

Highest pathogenic variant AF is 0.0000723

Variants in HMGCL

This is a list of pathogenic ClinVar variants found in the HMGCL region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-23801977-C-T		UDPglucose-4-epimerase deficiency • Deficiency of hydroxymethylglutaryl-CoA lyase	Benign (Jan 12, 2018)
1-23802049-C-T		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Jan 13, 2018)
1-23802075-C-T		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Jan 12, 2018)
1-23802097-C-T		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Jan 12, 2018)
1-23802125-C-G		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Jan 13, 2018)
1-23802173-A-G		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Jan 13, 2018)
1-23802174-C-A		Deficiency of hydroxymethylglutaryl-CoA lyase	Likely benign (Jan 12, 2018)
1-23802269-G-C		Deficiency of hydroxymethylglutaryl-CoA lyase	Likely benign (Apr 11, 2023)
1-23802359-C-T		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Jan 13, 2018)
1-23802464-C-G		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (May 09, 2018)
1-23802464-C-T		Deficiency of hydroxymethylglutaryl-CoA lyase	Likely benign (Oct 30, 2023)
1-23802465-A-G		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Dec 14, 2017)
1-23802472-A-G		Deficiency of hydroxymethylglutaryl-CoA lyase	Likely benign (Aug 21, 2021)
1-23802475-G-C		Deficiency of hydroxymethylglutaryl-CoA lyase	Likely benign (Dec 05, 2022)
1-23802479-G-T		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Jul 03, 2022)
1-23802481-C-T		Deficiency of hydroxymethylglutaryl-CoA lyase	Likely benign (Jun 14, 2023)
1-23802483-G-A		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Jun 09, 2017)
1-23802491-T-C		Deficiency of hydroxymethylglutaryl-CoA lyase • Inborn genetic diseases	Uncertain significance (May 23, 2023)
1-23802496-G-C		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Sep 01, 2021)
1-23802499-A-T		Deficiency of hydroxymethylglutaryl-CoA lyase	Likely benign (Dec 27, 2023)
1-23802508-G-A		Deficiency of hydroxymethylglutaryl-CoA lyase	Likely benign (Jan 13, 2018)
1-23802508-G-C		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (Apr 27, 2017)
1-23802510-T-C		Inborn genetic diseases	Uncertain significance (Dec 13, 2022)
1-23802520-A-G		Deficiency of hydroxymethylglutaryl-CoA lyase • HMGCL-related disorder	Likely benign (Jan 13, 2024)
1-23802521-C-T		Deficiency of hydroxymethylglutaryl-CoA lyase	Uncertain significance (May 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HMGCL	protein_coding	protein_coding	ENST00000374490	9	36736

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000256	0.758	125699	0	49	125748	0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.460	157	174	0.902	0.00000900	2086
Missense in Polyphen		54	74.291	0.72687		903
Synonymous	-0.128	67	65.7	1.02	0.00000362	672
Loss of Function	1.23	11	16.4	0.672	7.92e-7	198

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000770	0.000770
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000114	0.000114
Middle Eastern	0.000109	0.000109
South Asian	0.000392	0.000392
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Key enzyme in ketogenesis (ketone body formation). 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. {ECO:0000269|PubMed:22847177, ECO:0000269|PubMed:22865860, ECO:0000269|PubMed:8566388}.
• Pathway: Butanoate metabolism - Homo sapiens (human);Peroxisome - Homo sapiens (human);Synthesis and degradation of ketone bodies - Homo sapiens (human);Valine, leucine and isoleucine degradation - Homo sapiens (human);3-Methylglutaconic Aciduria Type I;Valine, Leucine and Isoleucine Degradation;2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency;Isovaleric Aciduria;3-Methylcrotonyl Coa Carboxylase Deficiency Type I;Propionic Acidemia;Maple Syrup Urine Disease;3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency;Isobutyryl-coa dehydrogenase deficiency;3-hydroxyisobutyric aciduria;3-hydroxyisobutyric acid dehydrogenase deficiency;Isovaleric acidemia;Methylmalonate Semialdehyde Dehydrogenase Deficiency;Succinyl CoA: 3-ketoacid CoA transferase deficiency;Methylmalonic Aciduria;3-Methylglutaconic Aciduria Type IV;3-Methylglutaconic Aciduria Type III;Ketone Body Metabolism;Butyrate Metabolism;Beta-Ketothiolase Deficiency;Synthesis and Degradation of Ketone Bodies;Amino Acid metabolism;ketogenesis;Butanoate metabolism;Metabolism of lipids;Metabolism of proteins;leucine degradation;Metabolism;Peroxisomal protein import;Synthesis of Ketone Bodies;Ketone body metabolism;Valine, leucine and isoleucine degradation;Pyruvate metabolism;Valine Leucine Isoleucine degradation (Consensus)

Recessive Scores

• pRec: 0.246

Intolerance Scores

• loftool: 0.276
• rvis_EVS: -0.6
• rvis_percentile_EVS: 17.75

Haploinsufficiency Scores

• pHI: 0.0855
• hipred: N
• hipred_score: 0.319
• ghis: 0.534

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Hmgcl
• Phenotype: growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: liver development;leucine catabolic process;protein targeting to peroxisome;lipid metabolic process;acyl-CoA metabolic process;mitochondrion organization;response to nutrient;response to starvation;ketone body biosynthetic process;protein tetramerization;response to fatty acid
• Cellular component: mitochondrion;mitochondrial matrix;peroxisome;peroxisomal matrix;cytosol
• Molecular function: fatty-acyl-CoA binding;magnesium ion binding;hydroxymethylglutaryl-CoA lyase activity;signaling receptor binding;manganese ion binding;carboxylic acid binding;protein homodimerization activity;metal ion binding