3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Summary

3-hydroxy-3-methylglutaryl-CoA synthase deficiency (MONDO:0011614) is a disease caused by HMGCS2 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HMGCS2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 251
• Phenotypes (HPO): 3
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001939	Abnormality of metabolism/homeostasis	Very frequent (80-99%)
HP:0001943	Hypoglycemia	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-hydroxy-3-methylglutaryl-CoA synthase deficiency
Mondo ID	MONDO:0011614
MeSH	C567784
OMIM	605911
Orphanet	35701
DOID	DOID:0081168
SNOMED CT	725286002
UMLS	C2751532
MedGen	414399
GARD	0002712
Is cancer (heuristic)	no

Also known as: 3-hydroxy-3-methylglutaryl-CoA synthase deficiency · 3-hydroxy-3-methylglutaryl-CoA synthase-2 deficiency · HMG CoA synthetase deficiency · HMG-CoA synthase deficiency · HMG-CoA synthase-2 deficiency · HMGCS2D

Data availability: 251 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of energy metabolism › disorder of fatty acid and ketone body metabolism › disorder of fatty acid oxidation and ketogenesis › 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Related subtypes (9): very long chain acyl-CoA dehydrogenase deficiency, carnitine-acylcarnitine translocase deficiency, systemic primary carnitine deficiency disease, 3-hydroxy-3-methylglutaric aciduria, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, acyl-CoA dehydrogenase 9 deficiency, acyl-CoA dehydrogenase deficiency, 3-hydroxyacyl-CoA dehydrogenase deficiency, long chain acyl-CoA dehydrogenase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

251 retrieved; paginated sample, class counts are floors:

98 uncertain significance, 71 likely benign, 28 pathogenic, 20 likely pathogenic, 16 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 6 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120051	NM_005518.4(HMGCS2):c.72dup (p.Pro25fs)	HMGCS2	Pathogenic	no assertion criteria provided
1184725	NM_005518.4(HMGCS2):c.851-2A>C	HMGCS2	Pathogenic	no assertion criteria provided
1327460	NM_005518.4(HMGCS2):c.39dup (p.Leu14fs)	HMGCS2	Pathogenic	criteria provided, single submitter
1327461	NM_005518.4(HMGCS2):c.717T>G (p.Tyr239Ter)	HMGCS2	Pathogenic	criteria provided, single submitter
1327465	NM_005518.4(HMGCS2):c.1394del (p.Asn465fs)	HMGCS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1327467	NM_005518.4(HMGCS2):c.1017-2A>G	HMGCS2	Pathogenic	criteria provided, single submitter
1327469	NM_005518.4(HMGCS2):c.788del (p.Leu263fs)	HMGCS2	Pathogenic	criteria provided, single submitter
1424635	NM_005518.4(HMGCS2):c.1030G>T (p.Glu344Ter)	HMGCS2	Pathogenic	criteria provided, single submitter
1453176	NM_005518.4(HMGCS2):c.1016+1G>A	HMGCS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1458530	NC_000001.10:g.(?120311344)(120311467_?)del	HMGCS2	Pathogenic	criteria provided, single submitter
2080601	NM_005518.4(HMGCS2):c.682C>T (p.Arg228Ter)	HMGCS2	Pathogenic	criteria provided, single submitter
2149225	NM_005518.4(HMGCS2):c.1354C>T (p.Arg452Ter)	HMGCS2	Pathogenic	criteria provided, single submitter
2194069	NM_005518.4(HMGCS2):c.726C>G (p.Tyr242Ter)	HMGCS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280473	NM_005518.4(HMGCS2):c.862C>T (p.Arg288Ter)	HMGCS2	Pathogenic	criteria provided, multiple submitters, no conflicts
2964858	NM_005518.4(HMGCS2):c.1229dup (p.Ser411fs)	HMGCS2	Pathogenic	criteria provided, single submitter
3693126	NM_005518.4(HMGCS2):c.634G>T (p.Gly212Ter)	HMGCS2	Pathogenic	criteria provided, single submitter
3730215	NM_005518.4(HMGCS2):c.810C>G (p.Tyr270Ter)	HMGCS2	Pathogenic	criteria provided, single submitter
449457	NM_005518.4(HMGCS2):c.1162G>A (p.Gly388Arg)	HMGCS2	Pathogenic	criteria provided, multiple submitters, no conflicts
452101	NM_005518.4(HMGCS2):c.1502G>C (p.Arg501Pro)	HMGCS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4706223	NM_005518.4(HMGCS2):c.536G>A (p.Trp179Ter)	HMGCS2	Pathogenic	criteria provided, single submitter
4742331	NM_005518.4(HMGCS2):c.850+1G>A	HMGCS2	Pathogenic	criteria provided, single submitter
488532	NM_005518.4(HMGCS2):c.1017-2del	HMGCS2	Pathogenic	criteria provided, single submitter
488533	NM_005518.4(HMGCS2):c.772del (p.Ser258fs)	HMGCS2	Pathogenic	criteria provided, single submitter
644135	NM_005518.4(HMGCS2):c.850+2T>C	HMGCS2	Pathogenic	criteria provided, single submitter
827683	NM_005518.4(HMGCS2):c.1480C>T (p.Arg494Ter)	HMGCS2	Pathogenic	criteria provided, single submitter
832206	NC_000001.11:g.(?119768721)(119768864_?)del	HMGCS2	Pathogenic	criteria provided, single submitter
859738	NM_005518.4(HMGCS2):c.559+1G>A	HMGCS2	Pathogenic	criteria provided, single submitter
859739	NM_005518.4(HMGCS2):c.1090T>A (p.Phe364Ile)	HMGCS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
915425	NM_005518.4(HMGCS2):c.181_182insCCAATATGGCCCTGGAGGCCAA (p.Val61fs)	HMGCS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9257	NM_005518.4(HMGCS2):c.520T>C (p.Phe174Leu)	HMGCS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
HMGCS2	Definitive	Autosomal recessive	3-hydroxy-3-methylglutaryl-CoA synthase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HMGCS2	Orphanet:35701	3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HMGCS2	HGNC:5008	ENSG00000134240	P54868	Hydroxymethylglutaryl-CoA synthase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HMGCS2	Hydroxymethylglutaryl-CoA synthase, mitochondrial	Catalyzes the first irreversible step in ketogenesis, condensing acetyl-CoA to acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HMGCS2	Enzyme (other)	yes	2.3.3.10	HMG_CoA_synt_AS, HMG_CoA_synthase_euk, HMG_CoA_synth_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HMGCS2	201	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HMGCS2	2,526

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HMGCS2	P54868	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of Ketone Bodies	1	1427.5×	0.002	HMGCS2
Mitochondrial protein degradation	1	114.2×	0.011	HMGCS2
PPARA activates gene expression	1	94.4×	0.011	HMGCS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to monosaccharide	1	16852.0×	0.001	HMGCS2
response to triglyceride	1	8426.0×	0.001	HMGCS2
farnesyl diphosphate biosynthetic process, mevalonate pathway	1	5617.3×	0.001	HMGCS2
response to prostaglandin F	1	5617.3×	0.001	HMGCS2
response to linoleic acid	1	5617.3×	0.001	HMGCS2
ketone body biosynthetic process	1	2808.7×	0.002	HMGCS2
acetyl-CoA metabolic process	1	2407.4×	0.002	HMGCS2
midgut development	1	2106.5×	0.002	HMGCS2
response to glucagon	1	1685.2×	0.002	HMGCS2
response to temperature stimulus	1	1532.0×	0.002	HMGCS2
response to metal ion	1	1532.0×	0.002	HMGCS2
multicellular organismal response to stress	1	1296.3×	0.002	HMGCS2
response to growth hormone	1	1123.5×	0.002	HMGCS2
cellular response to fatty acid	1	702.2×	0.003	HMGCS2
cellular response to glucocorticoid stimulus	1	624.1×	0.003	HMGCS2
response to cAMP	1	510.7×	0.003	HMGCS2
response to testosterone	1	468.1×	0.003	HMGCS2
response to starvation	1	468.1×	0.003	HMGCS2
cholesterol biosynthetic process	1	421.3×	0.004	HMGCS2
adipose tissue development	1	401.2×	0.004	HMGCS2
cellular response to amino acid stimulus	1	306.4×	0.004	HMGCS2
response to nutrient	1	295.6×	0.004	HMGCS2
liver development	1	221.7×	0.006	HMGCS2
lung development	1	198.3×	0.006	HMGCS2
cellular response to insulin stimulus	1	170.2×	0.007	HMGCS2
response to ethanol	1	146.5×	0.008	HMGCS2
kidney development	1	140.4×	0.008	HMGCS2
cellular response to lipopolysaccharide	1	98.0×	0.011	HMGCS2
response to xenobiotic stimulus	1	69.1×	0.014	HMGCS2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HMGCS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HMGCS2	2.3.3.10	hydroxymethylglutaryl-CoA synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HMGCS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HMGCS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening