HMGCS2

protein-coding

3-hydroxy-3-methylglutaryl-CoA synthase 2

Gene summary

The protein encoded by this gene belongs to the HMG-CoA synthase family. It is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting. Mutations in this gene are associated with HMG-CoA synthase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

MANE transcript

NM_005518.4

Inheritance

ClinVar variants

P:60U:135B:74

Top phenotype

3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr1:119,748,002-119,768,905

External References & Databases

Ensembl (ENSG00000134240)

Transcript & Mutation Effects

hg38 • Region Span ~20.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3-hydroxy-3-methylglutaryl-CoA synthase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011614

Submitter: PanelApp Australia

3-hydroxy-3-methylglutaryl-CoA synthase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011614

Submitter: Orphanet

3-hydroxy-3-methylglutaryl-CoA synthase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011614

Submitter: ClinGen

3-hydroxy-3-methylglutaryl-CoA synthase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011614

Submitter: G2P

3-hydroxy-3-methylglutaryl-CoA synthase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011614

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: Specific dietary measures (especially avoidance of fasting) as well as other treatments may be beneficial, both in well and decompensated state

Refs: 9337379; 9727719; 11228257; 11479731; 16601895; 39798988,

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HMGCS2 variants in ClinVar

6 Conditions Cataloged

3-hydroxy-3-methylglutaryl-CoA synthase deficiencyTotal: 240

Inborn genetic diseasesTotal: 67

not providedTotal: 60

not specifiedTotal: 22

HMGCS2-related disorderTotal: 16

HMGCS2-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005518.4. 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				68 clinvar		68
missense	2 clinvar	23 clinvar	135 clinvar	6 clinvar		166
nonsense	9 clinvar	4 clinvar				13
start loss						0
frameshift	8 clinvar	4 clinvar				12
splice donor/acceptor (+/-2bp)	7 clinvar	3 clinvar				10
Total	26	34	135	74	0	269

Highest pathogenic variant AF is 0.0002509275

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005518.4	RefSeq	NP_005509.1	9	MANE Select
ENST00000369406.8	Ensembl	ENSP00000358414.3	9	MANE Select
NM_001166107.1	RefSeq	NP_001159579.1	8	Standard
ENST00000544913.2	Ensembl	ENSP00000439495.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Butanoate metabolism - Homo sapiens (human)
Synthesis and degradation of ketone bodies - Homo sapiens (human)
Terpenoid backbone biosynthesis - Homo sapiens (human)
PPAR signaling pathway - Homo sapiens (human)
Valine, leucine and isoleucine degradation - Homo sapiens (human)

Biological Process

acetyl-CoA metabolic process
cholesterol biosynthetic process
farnesyl diphosphate biosynthetic process, mevalonate pathway
regulation of lipid metabolic process
ketone body biosynthetic process

Molecular Function

hydroxymethylglutaryl-CoA synthase activity

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369406
Coding exons: 9
Length: 20910
Individuals with no LoFs: 125647
Homozygous LoFs: 0
Heterozygous LoFs: 101
Defined: 125748
p: 0.000402

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.191	289	280	1.03	0.0000170	3278
Missense (PolyPhen)		111	125.48	0.8846		1489
Synonymous	-1.63	132	110	1.20	0.00000617	1043
Loss of Function	0.736	23	27.1	0.848	0.00000175	280

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00043	0.00044	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.0011	0.0011	notable
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This enzyme condenses acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is the substrate for HMG-CoA reductase.;
Disease: DISEASE: 3-hydroxy-3-methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) [MIM:605911]: A metabolic disorder characterized by severe hypoketotic hypoglycemia, encephalopathy, and hepatomegaly. {ECO:0000269|PubMed:11228257, ECO:0000269|PubMed:11479731, ECO:0000269|PubMed:12647205}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.279

Intolerance Scores

LoFtool: 0.194
RVIS EVS: -0.87
RVIS percentile EVS: 10.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.965

Gene Damage Prediction

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