HMGCL

protein-coding

3-hydroxy-3-methylglutaryl-CoA lyase

Gene 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 deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

MANE transcript

NM_000191.3

Inheritance

ClinVar variants

P:112U:135B:152

Top phenotype

3-hydroxy-3-methylglutaryl-CoA lyase deficiency

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr1:23,801,885-23,838,620

External References & Databases

Ensembl (ENSG00000117305)

Transcript & Mutation Effects

hg38 • Region Span ~36.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3-hydroxy-3-methylglutaric aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009520

Submitter: Natera

3-hydroxy-3-methylglutaric aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009520

Submitter: Labcorp Genetics (formerly Invitae)

3-hydroxy-3-methylglutaric aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009520

Submitter: G2P

3-hydroxy-3-methylglutaric aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009520

Submitter: Myriad Women's Health

3-hydroxy-3-methylglutaric aciduriaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009520

Submitter: ClinGen

3-hydroxy-3-methylglutaric aciduriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009520

Submitter: Orphanet

3-hydroxy-3-methylglutaric aciduriaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009520

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

3-hydroxy-3-methylglutaryl-CoA lyase deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: 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

Refs: 1256504; 1000856; 91680; 85928; 6156427; 6112838; 6489380; 6475954; 3099065; 3128690; 2246860; 8440722; 8617516; 11129331; 17692550; 19177531; 19932602

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HMGCL variants in ClinVar

7 Conditions Cataloged

Deficiency of hydroxymethylglutaryl-CoA lyaseTotal: 474

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiencyTotal: 73

not providedTotal: 62

Inborn genetic diseasesTotal: 38

HMGCL-related disorderTotal: 21

not specifiedTotal: 20

HMGCL-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000191.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	146 clinvar	1 clinvar	153
missense	2 clinvar	19 clinvar	124 clinvar	5 clinvar		150
nonsense	10 clinvar	12 clinvar	1 clinvar			23
start loss		1 clinvar	1 clinvar			2
frameshift	24 clinvar	19 clinvar	2 clinvar			45
splice donor/acceptor (+/-2bp)	4 clinvar	21 clinvar	1 clinvar			26
Total	40	72	135	151	1	399

Highest pathogenic variant AF is 0.00008735756

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000191.3	RefSeq	NP_000182.2	9	MANE Select
ENST00000374490.8	Ensembl	ENSP00000363614.3	9	MANE Select
NM_001166059.2	RefSeq	NP_001159531.1	7	Standard
ENST00000235958.4	Ensembl	ENSP00000235958.4	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

liver development
leucine catabolic process
protein targeting to peroxisome
lipid metabolic process
acyl-CoA metabolic process

Molecular Function

fatty-acyl-CoA binding
magnesium ion binding
hydroxymethylglutaryl-CoA lyase activity
signaling receptor binding
manganese ion binding

Cellular Component

mitochondrion
mitochondrial matrix
peroxisome
peroxisomal matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374490
Coding exons: 9
Length: 36736
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.460	157	174	0.902	0.00000900	2086
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00046	0.00046	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.00039	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.246

Intolerance Scores

LoFtool: 0.276
RVIS EVS: -0.6
RVIS percentile EVS: 17.75

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

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