HMGCR

3-hydroxy-3-methylglutaryl-CoA reductase

Basic information

Region (hg38): 5:75336329-75364001

Links

ENSG00000113161

∙ NCBI:3156 ∙ OMIM:142910 ∙ HGNC:5006 ∙ Uniprot:P04035 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

muscular dystrophy, limb-girdle, autosomal recessive 28 (Strong), mode of inheritance: AR
muscular dystrophy, limb-girdle, autosomal recessive 28 (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Statins, efficacy of; Myopathy, limb-girdle, autosomal recessive 28	AD/AR	Musculoskeletal; Pharmacogenomic	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)	Musculoskeletal	15199031; 15367547; 24001602; 36745799

ClinVar

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

Inborn_genetic_diseases (48 variants)
Muscular_dystrophy,_limb-girdle,_autosomal_recessive_28 (8 variants)
not_provided (6 variants)
HMGCR-related_disorder (5 variants)
Limb-girdle_muscular_dystrophy (1 variants)
Basal_cell_nevus_syndrome_1 (1 variants)
Autoinflammatory_syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HMGCR gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000859.3. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous				5 clinvar		5
missense	3 clinvar	3 clinvar	48 clinvar	2 clinvar	1 clinvar	57
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	3	3	48	7	1

Highest pathogenic variant AF is 0.00000499289

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HMGCR	protein_coding	protein_coding	ENST00000287936	19	25776

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.00139	125733	0	14	125747	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.76	262	498	0.526	0.0000262	5816
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.0000617	0.0000615
Middle Eastern	0.000163	0.000163
South Asian	0.0000808	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

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.;
Pathway: Mevalonate pathway;Bile secretion - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Terpenoid backbone biosynthesis - Homo sapiens (human);Bisphosphonate Pathway, Pharmacodynamics;Metformin Pathway, Pharmacodynamic;Statin 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;AMP-activated Protein Kinase (AMPK) Signaling;Target Of Rapamycin (TOR) Signaling;Cholesterol Biosynthesis;Sterol Regulatory Element-Binding Proteins (SREBP) signalling;Integrated Breast Cancer Pathway;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);Demo complete;Demo;Statin Pathway;Metabolism of lipids;Regulation of cholesterol biosynthesis by SREBP (SREBF);Squalene and cholesterol biosynthesis;Metabolism;superpathway of cholesterol biosynthesis;Metabolism of steroids;Steroids metabolism;Cholesterol biosynthesis;Activation of gene expression by SREBF (SREBP);mevalonate pathway;superpathway of geranylgeranyldiphosphate biosynthesis I (via mevalonate) (Consensus)

Recessive Scores

pRec: 0.617

Intolerance Scores

loftool: 0.203
rvis_EVS: -0.49
rvis_percentile_EVS: 22.36

Haploinsufficiency Scores

pHI: 0.894
hipred: Y
hipred_score: 0.783
ghis: 0.637

Essentials

essential_gene_CRISPR: E
essential_gene_CRISPR2: E
essential_gene_gene_trap: E
gene_indispensability_pred: E
gene_indispensability_score: 0.998

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Hmgcr
Phenotype: liver/biliary system phenotype; growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; homeostasis/metabolism phenotype;

Zebrafish Information Network

Gene name: hmgcrb
Affected structure: ethmoid cartilage
Phenotype tag: abnormal
Phenotype quality: shortened

Gene ontology

Biological process: cholesterol biosynthetic process;ubiquinone metabolic process;aging;response to nutrient;isoprenoid biosynthetic process;visual learning;negative regulation of striated muscle cell apoptotic process;positive regulation of cardiac muscle cell apoptotic process;coenzyme A metabolic process;sterol biosynthetic process;regulation of lipid metabolic process;positive regulation of stress-activated MAPK cascade;negative regulation of MAP kinase activity;myoblast differentiation;response to ethanol;regulation of cholesterol biosynthetic process;positive regulation of skeletal muscle tissue development;positive regulation of smooth muscle cell proliferation;protein tetramerization;oxidation-reduction process;negative regulation of wound healing;negative regulation of insulin secretion involved in cellular response to glucose stimulus;positive regulation of ERK1 and ERK2 cascade;negative regulation of blood vessel diameter
Cellular component: peroxisomal membrane;endoplasmic reticulum;endoplasmic reticulum membrane;integral component of membrane
Molecular function: hydroxymethylglutaryl-CoA reductase (NADPH) activity;protein binding;hydroxymethylglutaryl-CoA reductase activity;protein homodimerization activity;coenzyme binding;protein phosphatase 2A binding;NADPH binding