HMGCS2

3-hydroxy-3-methylglutaryl-CoA synthase 2

Basic information

Region (hg38): 1:119748001-119768905

Links

ENSG00000134240 ∙ NCBI:3158 ∙ OMIM:600234 ∙ HGNC:5008 ∙ Uniprot:P54868 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (Definitive), mode of inheritance: AR
• 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (Strong), mode of inheritance: AR
• 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (Strong), mode of inheritance: AR
• 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (Supportive), mode of inheritance: AR
• 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency	AR	Biochemical	Specific dietary measures (especially avoidance of fasting) as well as other treatments may be beneficial, both in well and decompensated state	Biochemical; Neurologic	9337379; 9727719; 11228257; 11479731; 16601895

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HMGCS2 gene.

• 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (197 variants)
• not provided (61 variants)
• Inborn genetic diseases (21 variants)
• not specified (17 variants)
• HMGCS2-related condition (3 variants)
• PHGDH deficiency (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HMGCS2 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			1	37		38
missense	3	9	99	1		112
nonsense	6	2				8
start loss						0
frameshift	5	3				8
inframe indel						0
splice donor/acceptor (+/-2bp)	5	1				6
splice region			4	4	1	9
non coding			5	30	23	58
Total	19	15	105	68	23

Highest pathogenic variant AF is 0.0000920

Variants in HMGCS2

This is a list of pathogenic ClinVar variants found in the HMGCS2 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-119748025-C-T		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Benign (Apr 27, 2017)
1-119748055-C-T		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Benign (Apr 27, 2017)
1-119748082-C-T		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Uncertain significance (Jan 12, 2018)
1-119748515-T-G		3-hydroxy-3-methylglutaryl-CoA synthase deficiency • PHGDH deficiency	Likely benign (Jun 14, 2016)
1-119748606-TTTCACAAA-T			Likely benign (Jul 24, 2020)
1-119748682-G-A		PHGDH deficiency • 3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Likely benign (Jun 14, 2016)
1-119748692-G-A		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Uncertain significance (Jan 13, 2018)
1-119748708-G-T		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Uncertain significance (Jan 12, 2018)
1-119748769-T-C		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Likely benign (Jan 13, 2018)
1-119748835-T-G		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Benign (Apr 27, 2017)
1-119748848-TAAAC-T		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Uncertain significance (Jun 14, 2016)
1-119748857-A-G		not specified	Benign (Apr 04, 2014)
1-119750546-T-C			Benign (Jul 27, 2018)
1-119750729-T-C			Benign (Jun 29, 2018)
1-119750744-T-C			Benign (Jun 23, 2018)
1-119750771-C-G			Likely benign (Jun 23, 2018)
1-119750807-C-T		3-hydroxy-3-methylglutaryl-CoA synthase deficiency • HMGCS2-related disorder	Conflicting classifications of pathogenicity (Jan 01, 2024)
1-119750808-G-A		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Likely benign (Dec 31, 2022)
1-119750812-C-T		Inborn genetic diseases	Uncertain significance (Feb 11, 2022)
1-119750813-G-A		Inborn genetic diseases	Uncertain significance (Dec 14, 2022)
1-119750815-C-T		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Uncertain significance (May 17, 2022)
1-119750816-G-A		3-hydroxy-3-methylglutaryl-CoA synthase deficiency • Inborn genetic diseases	Uncertain significance (Mar 26, 2024)
1-119750827-C-G		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Conflicting classifications of pathogenicity (Mar 02, 2023)
1-119750830-C-T		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Pathogenic/Likely pathogenic (May 27, 2022)
1-119750831-G-A		3-hydroxy-3-methylglutaryl-CoA synthase deficiency	Uncertain significance (Jan 24, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HMGCS2	protein_coding	protein_coding	ENST00000369406	9	20910

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.34e-14	0.0899	125647	0	101	125748	0.000402

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.191	289	280	1.03	0.0000170	3278
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00143	0.00143
Ashkenazi Jewish	0.00	0.00
East Asian	0.000435	0.000435
Finnish	0.00	0.00
European (Non-Finnish)	0.000248	0.000246
Middle Eastern	0.000435	0.000435
South Asian	0.00111	0.00111
Other	0.000489	0.000489

dbNSFP

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.
• Pathway: 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);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;Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha);Synthesis and Degradation of Ketone Bodies;Amino Acid metabolism;PPAR signaling pathway;Liver steatosis AOP;ketogenesis;Butanoate metabolism;Metabolism of lipids;Metabolism;superpathway of cholesterol biosynthesis;Synthesis of Ketone Bodies;Ketone body metabolism;Butanoate metabolism;Valine Leucine Isoleucine degradation;Validated targets of C-MYC transcriptional repression;mevalonate pathway;superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate) (Consensus)

Recessive Scores

• pRec: 0.279

Intolerance Scores

• loftool: 0.194
• rvis_EVS: -0.87
• rvis_percentile_EVS: 10.73

Haploinsufficiency Scores

• pHI: 0.200
• hipred: N
• hipred_score: 0.219
• ghis: 0.546

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.965

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hmgcs2

Gene ontology

• Biological process: acetyl-CoA metabolic process;cholesterol biosynthetic process;farnesyl diphosphate biosynthetic process, mevalonate pathway;regulation of lipid metabolic process;ketone body biosynthetic process
• Cellular component: mitochondrion;mitochondrial matrix
• Molecular function: hydroxymethylglutaryl-CoA synthase activity