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

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.

• Limb-girdle muscular dystrophy (1 variants)
• Muscular dystrophy, limb-girdle, autosomal recessive 28 (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.

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				3		3
missense	1		16		1	18
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				1		1
non coding				2	1	3
Total	1	0	16	5	2

Variants in HMGCR

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

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

Position	Type	Phenotype	Significance	ClinVar
5-75342737-T-C		HMGCR-related disorder	Likely benign (Mar 01, 2019)
5-75344257-T-A		Inborn genetic diseases	Uncertain significance (May 05, 2023)
5-75344336-A-G		Muscular dystrophy, limb-girdle, autosomal recessive 28	Pathogenic (Jun 21, 2023)
5-75345615-G-A		Inborn genetic diseases	Uncertain significance (Mar 01, 2023)
5-75347030-A-T		-	no classification for the single variant (-)
5-75347264-G-A		Inborn genetic diseases	Uncertain significance (Jan 11, 2023)
5-75350103-C-T		HMGCR-related disorder	Likely benign (Apr 18, 2019)
5-75350791-T-A		HMGCR-related disorder	Likely benign (Aug 09, 2019)
5-75350838-C-T		Inborn genetic diseases	Uncertain significance (Aug 17, 2021)
5-75350870-A-G		Inborn genetic diseases	Uncertain significance (Jun 14, 2023)
5-75350940-A-C		HMGCR-related disorder	Benign (Aug 29, 2019)
5-75351073-T-A		Inborn genetic diseases	Uncertain significance (Nov 08, 2022)
5-75351155-G-C		Inborn genetic diseases	Uncertain significance (Jan 20, 2023)
5-75351228-T-C		Inborn genetic diseases	Uncertain significance (May 11, 2022)
5-75351540-A-G		Inborn genetic diseases	Uncertain significance (Jan 25, 2024)
5-75351561-C-T		Muscular dystrophy, limb-girdle, autosomal recessive 28	Pathogenic (Jun 21, 2023)
5-75351562-G-A		Muscular dystrophy, limb-girdle, autosomal recessive 28	Pathogenic (Jun 21, 2023)
5-75352778-A-T		Low density lipoprotein cholesterol level quantitative trait locus 3	association (Mar 20, 2008)
5-75354650-CCTT-C		Muscular dystrophy, limb-girdle, autosomal recessive 28	Pathogenic (Jun 21, 2023)
5-75354693-C-T		Inborn genetic diseases	Uncertain significance (Feb 11, 2022)
5-75355083-A-G		Inborn genetic diseases	Uncertain significance (Jun 28, 2022)
5-75355133-T-A		Inborn genetic diseases	Uncertain significance (Dec 21, 2023)
5-75355435-G-A		Inborn genetic diseases	Uncertain significance (Jun 12, 2023)
5-75355441-G-A		Inborn genetic diseases	Uncertain significance (Sep 08, 2023)
5-75355509-G-A		Muscular dystrophy, limb-girdle, autosomal recessive 28	Pathogenic (Jun 21, 2023)

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