HMGCR
protein-coding3-hydroxy-3-methylglutaryl-CoA reductase
Gene summary
HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and is regulated via a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~27.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015152
Submitter: ClinGen
*HMGCR* was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 2023 (Yogev Y et al., PMID:36745799). At least 10 variants (eight missense, one in-frame deletion and one intronic) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least six probands in two publications (PMID:36745799, PMID:37167966). Variants in this gene segregated with disease in nine additional family members. One large consanguineous kindred is reported with an LOD score of 4.8204 (PMID:36745799). The mechanism for disease is unknown. This gene-disease association is supported by a mouse model recapitulating the human limb-girdle muscular dystrophy phenotype (PMID:26381177). Using skeletal muscle-specific *HMGCR* knockout mice the authors demonstrated that mice missing *HMGCR* expression in their skeletal muscle exhibit muscle weakness, exercise intolerance, elevated creatine kinase levels and abnormal/myopathic muscle biopsy. These clinical features are also seen in the human probands included in this curation. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Muscular Dystrophies and Myopathies Gene Curation Expert Panel on the meeting date 13 August 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0015152
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0957270
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0957270
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
Intervention: Musculoskeletal; Pharmacogenomic
Rationale: Related to Statins, efficacy of, selection and dosage of cholesterol-lowering medications may be impacted by genotyping results; Individuals with Myopathy, limb-girdle, adult-onset have been described as responsive to medical management (with mevalonolactone)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HMGCR variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000859.3. 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 | 1 | 10 | 1 | 12 | ||
| missense | 2 | 4 | 61 | 3 | 1 | 71 |
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 7 | 7 | ||||
| Total | 2 | 5 | 70 | 13 | 2 | 92 |
Highest pathogenic variant AF is 0.0000049928913
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000850.1 | 19 | MANE Select | |
| Ensembl | ENSP00000287936.4 | 19 | MANE Select | |
| RefSeq | NP_001124468.1 | 18 | Standard | |
| RefSeq | NP_001351116.1 | 19 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hmgcrb | Danio rerio | Structure: ethmoid cartilage Quality: shortened abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mevalonate pathway
- Bile secretion - Homo sapiens (human)
- AMPK signaling pathway - Homo sapiens (human)
- Terpenoid backbone biosynthesis - Homo sapiens (human)
- Bisphosphonate Pathway, Pharmacodynamics
Biological Process
- cholesterol biosynthetic process
- ubiquinone metabolic process
- aging
- response to nutrient
- isoprenoid biosynthetic process
Molecular Function
- hydroxymethylglutaryl-CoA reductase (NADPH) activity
- protein binding
- hydroxymethylglutaryl-CoA reductase activity
- protein homodimerization activity
- coenzyme binding
Cellular Component
- peroxisomal membrane
- endoplasmic reticulum
- endoplasmic reticulum membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000287936
- Coding exons
- 19
- Length
- 25776
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 14
- Defined
- 125747
- p
- 0.0000557
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.76 | 262 | 498 | 0.526 | 0.0000262 | 5816 |
| Missense (PolyPhen) | 63 | 184.75 | 0.34099 | 2115 | ||
| Synonymous | 1.01 | 147 | 163 | 0.900 | 0.00000817 | 1746 |
| Loss of Function | 5.43 | 6 | 45.6 | 0.132 | 0.00000252 | 545 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.000081 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins.;
Recessive Scores
- pRec
- 0.617
Intolerance Scores
- LoFtool
- 0.203
- RVIS EVS
- -0.49
- RVIS percentile EVS
- 22.36
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.998
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |