HMGCS1

3-hydroxy-3-methylglutaryl-CoA synthase 1

Basic information

Region (hg38): 5:43287469-43313512

Previous symbols: [ "HMGCS" ]

Links

ENSG00000112972 ∙ NCBI:3157 ∙ OMIM:142940 ∙ HGNC:5007 ∙ Uniprot:Q01581 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HMGCS1 gene.

• Rigid spine syndrome (7 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HMGCS1 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	1
missense	6		9			15
nonsense						0
start loss						0
frameshift	1					1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	7	0	9	0	1

Highest pathogenic variant AF is 0.00000657

Variants in HMGCS1

This is a list of pathogenic ClinVar variants found in the HMGCS1 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-43292488-T-C		not specified	Uncertain significance (May 30, 2024)
5-43292524-C-T		not specified	Uncertain significance (Dec 19, 2022)
5-43292608-A-G		Rigid spine syndrome	Pathogenic (Sep 20, 2023)
5-43292614-T-C		not specified	Likely benign (May 31, 2024)
5-43292868-C-T		Rigid spine syndrome	Pathogenic (Sep 20, 2023)
5-43292887-C-T		not specified	Uncertain significance (Apr 01, 2022)
5-43294064-G-C		not specified	Uncertain significance (Jan 23, 2024)
5-43294090-C-T			Benign (Feb 24, 2021)
5-43295767-C-A		Rigid spine syndrome	Pathogenic (Sep 20, 2023)
5-43295854-C-G		Rigid spine syndrome	Pathogenic (Sep 20, 2023)
5-43295876-T-C		not specified	Uncertain significance (Apr 01, 2024)
5-43297061-C-G		not specified	Uncertain significance (Nov 09, 2021)
5-43298596-C-T		not specified	Uncertain significance (Oct 10, 2023)
5-43298620-CAG-C		Rigid spine syndrome	Pathogenic (Sep 20, 2023)
5-43298757-A-G		Rigid spine syndrome	Pathogenic (Sep 20, 2023)
5-43298823-G-A		not specified	Uncertain significance (Dec 15, 2022)
5-43298872-C-A		not specified	Uncertain significance (Feb 26, 2024)
5-43298880-T-A		Rigid spine syndrome	Pathogenic (Sep 20, 2023)
5-43298920-C-A		not specified	Uncertain significance (Dec 28, 2022)
5-43298920-C-G		not specified	Uncertain significance (Jul 13, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HMGCS1	protein_coding	protein_coding	ENST00000325110	9	24118

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.998	0.00176	125720	0	4	125724	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.04	135	277	0.487	0.0000136	3387
Missense in Polyphen		25	109.88	0.22753		1309
Synonymous	2.27	68	96.3	0.706	0.00000457	1011
Loss of Function	4.24	1	22.9	0.0436	0.00000106	311

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000290	0.0000290
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000178	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000163	0.000163

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.
• Pathway: Mevalonate pathway;Butanoate metabolism - Homo sapiens (human);Synthesis and degradation of ketone bodies - Homo sapiens (human);Terpenoid backbone biosynthesis - Homo sapiens (human);Valine, leucine and isoleucine degradation - Homo sapiens (human);Bisphosphonate Pathway, Pharmacodynamics;Simvastatin Action Pathway;Pravastatin Action Pathway;Atorvastatin Action Pathway;Hyper-IgD syndrome;Cholesteryl ester storage disease;Lysosomal Acid Lipase Deficiency (Wolman Disease);Alendronate Action Pathway;Rosuvastatin Action Pathway;Lovastatin Action Pathway;Mevalonic aciduria;Wolman disease;Risedronate Action Pathway;Cerivastatin Action Pathway;Pamidronate Action Pathway;Fluvastatin Action Pathway;Smith-Lemli-Opitz Syndrome (SLOS);Chondrodysplasia Punctata II, X Linked Dominant (CDPX2);CHILD Syndrome;Desmosterolosis;Hypercholesterolemia;Steroid Biosynthesis;Zoledronate Action Pathway;Ibandronate Action Pathway;Cholesterol Biosynthesis;Sterol Regulatory Element-Binding Proteins (SREBP) signalling;SREBF and miR33 in cholesterol and lipid homeostasis;Activation of gene expression by SREBF (SREBP);Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha);Endochondral Ossification;ketogenesis;Butanoate metabolism;Metabolism of lipids;Regulation of cholesterol biosynthesis by SREBP (SREBF);Metabolism;superpathway of cholesterol biosynthesis;Metabolism of steroids;srebp control of lipid synthesis;Cholesterol biosynthesis;Valine Leucine Isoleucine degradation;Activation of gene expression by SREBF (SREBP);FOXA2 and FOXA3 transcription factor networks;mevalonate pathway;superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate) (Consensus)

Recessive Scores

• pRec: 0.402

Intolerance Scores

• loftool: 0.133
• rvis_EVS: -0.41
• rvis_percentile_EVS: 26.23

Haploinsufficiency Scores

• pHI: 0.378
• hipred: Y
• hipred_score: 0.728
• ghis: 0.661

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.928

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hmgcs1

Zebrafish Information Network

• Gene name: hmgcs1
• Affected structure: oligodendrocyte
• Phenotype tag: abnormal
• Phenotype quality: mislocalised dorsally

Gene ontology

• Biological process: liver development;acetyl-CoA metabolic process;lipid metabolic process;cholesterol biosynthetic process;brain development;male gonad development;response to low light intensity stimulus;farnesyl diphosphate biosynthetic process, mevalonate pathway;response to purine-containing compound;regulation of lipid metabolic process;response to vitamin E;response to drug;regulation of cholesterol biosynthetic process;response to tellurium ion;cellular response to follicle-stimulating hormone stimulus;cellular response to cholesterol;cellular response to low-density lipoprotein particle stimulus
• Cellular component: cytoplasm;cytosol
• Molecular function: hydroxymethylglutaryl-CoA synthase activity;drug binding;isomerase activity;protein homodimerization activity;organic acid binding