rs5742904

badMag 7.5

This is a variant in the APOB gene that changes a arginine to an leucine.

Key Literature Trait Associations

Familial Hypercholesterolemia

The APOB p.Arg3527Gln (R3527Q) variant — encoded by the rs5742904 T allele — causes familial defective apolipoprotein B-100 (FDB), an autosomal dominant form of familial hypercholesterolemia. In the Old Order Amish, each copy of the T allele raises LDL-C by approximately 74.9 mg/dL, with 12% of the Pennsylvania Amish community carrying the variant due to a founder effect. The condition is classified as Pathogenic/Likely pathogenic in ClinVar (2-star, multiple submitters). FDB typically presents with a milder lipoprotein phenotype than LDLR-mutation FH; some heterozygous carriers have LDL-C in the normal range, potentially leading to underdiagnosis by standard clinical criteria such as Med-Ped or Dutch Lipid Clinic Network scores.

Xu H et al. “Familial Hypercholesterolemia and Type 2 Diabetes in the Old Order Amish.” Diabetes (2017)
Allele T
OR —
β 74.900
p —
N 5,323
Preliminary work
Amish
Beheshti S et al. “Relationship of Familial Hypercholesterolemia and High Low-Density Lipoprotein Cholesterol to Ischemic Stroke: Copenhagen General Population Study.” Circulation (2018)
Allele T
OR —
p —
N 116,784
Preliminary work
European
Huang CC et al. “Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia.” Journal of Atherosclerosis and Thrombosis (2022)
Allele T
OR —
p —
N 750
Preliminary work
East Asian
Ejarque I et al. “Evaluation of clinical diagnosis criteria of familial ligand defective apoB 100 and lipoprotein phenotype comparison between LDL receptor gene mutations affecting ligand-binding domain and the R3500Q mutation of the apoB gene in patients from a South European population.” Translational Research : the Journal of Laboratory and Clinical Medicine (2008)
Allele T
OR —
p —
N 213
Candidate gene study
European
Williams KB et al. “Clinical characterization of familial hypercholesterolemia due to an amish founder mutation in Apolipoprotein B.” Bmc Cardiovascular Disorders (2022)
Allele T
OR —
p —
N 25
Candidate gene study
Amish
Snyder C et al. “Familial Hyperlipidemia Caused by Apolipoprotein B Mutation in the Pediatric Amish Population: A Mini Review.” Interventional Cardiology (2023)
Allele T
OR —
p —
Candidate gene study
Amish

LDL cholesterol

The rs5742904 T allele (APOB p.Arg3527Gln) substantially elevates circulating LDL cholesterol by impairing ApoB-100 binding to the LDL receptor, reducing LDL clearance. In the large Amish cohort, each copy of the T allele raised LDL-C by ~74.9 mg/dL. GWAS in the same Amish founder population also detected genome-wide significant associations between rs5742904 and multiple lipoprotein-related lipid species including cholesteryl esters, sphingomyelins, ceramides, and phosphatidylcholines, extending the variant's influence across the human lipidome. The T allele frequency is ~0.06 in the Amish but only ~0.0004 globally.

Xu H et al. “Familial Hypercholesterolemia and Type 2 Diabetes in the Old Order Amish.” Diabetes (2017)
Allele T
OR —
β 74.900
p —
N 5,323
Preliminary work
Amish
Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR —
p 1.0e-80
N 639
Small GWAS
Amish

Apolipoprotein B measurement

The rs5742904 T allele elevates circulating ApoB protein levels, consistent with reduced LDL receptor clearance of ApoB-100-containing particles. Clinical characterization in Amish carriers confirmed significantly elevated ApoB levels in heterozygotes compared to unaffected siblings. Elevated ApoB is an independent cardiovascular risk marker and is mechanistically central to the pathophysiology of FDB.

Williams KB et al. “Clinical characterization of familial hypercholesterolemia due to an amish founder mutation in Apolipoprotein B.” Bmc Cardiovascular Disorders (2022)
Allele T
OR —
p —
N 25
Candidate gene study
Amish
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GWAS Catalog Trait Associations (10)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

clinical treatment

Jiang L et al. “A generalized linear mixed model association tool for biobank-scale data.” Nature Genetics 53(11):1616-1621 (2021)
Allele T
OR 4.76
p 2.0e-20
N 456,276
Large GWAS
European

level of phosphatidylcholine

Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR 1.07
p 7.0e-19
N 650
Small GWAS
European

level of phosphatidylinositol

Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR 0.88
p 5.0e-13
N 650
Small GWAS
European

cholesteryl ester 20:3 measurement

Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR 0.85
p 5.0e-12
N 650
Small GWAS
European

cholesteryl ester 18:2 measurement

Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR 0.79
p 4.0e-11
N 650
Small GWAS
European

cholesteryl ester 18:3 measurement

Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR 0.77
p 2.0e-10
N 650
Small GWAS
European

level of phosphatidylethanolamine

Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR 0.73
p 4.0e-9
N 650
Small GWAS
European

level of ceramide

Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR 0.82
p 4.0e-11
N 650
Small GWAS
European

lipid measurement

Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR 1.01
p 3.0e-16
N 650
Small GWAS
European

sphingomyelin measurement

Montasser ME et al. “An Amish founder population reveals rare-population genetic determinants of the human lipidome.” Communications Biology 5(1):334 (2022)
Allele T
OR 0.93
p 7.0e-14
N 650
Small GWAS
European
▶

ClinVar annotation

Pathogenic★☆☆☆
67 submitters117 publications

Familial hypobetalipoproteinemia 1; Hypercholesterolemia, autosomal dominant, type B (FHCL2); Hypercholesterolemia, familial, 1

View on ClinVar →
▶

Research that mentions this SNP (2)

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Familial Defective Apolipoprotein B-100 and Increased Low-Density Lipoprotein Cholesterol and Coronary Artery Calcification in the Old Order Amish
AssociationN=1,504Haiqing Shen et al.(2010)· Archives of Internal Medicine

A genome-wide association study of 841 asymptomatic Amish individuals identified a cluster of SNPs on chromosome 2p strongly associated with LDL cholesterol levels (P < 10^-68 for rs4971516), with the APOB R3500Q mutation (rs5742904) accounting for 26% of LDL-C variation and conferring a 55-61 mg/dL increase in LDL-C levels and higher prevalence of coronary artery calcification in an independent replication sample of 663 individuals.

Traits studied:Coronary artery calcificationFamilial defective apolipoprotein B-100LDL cholesterol levels
PubMedDOIMetascience Observatory
▶
Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease
ReviewMarianne Abifadel et al.(2009)· Human Mutation

This review examines familial hypercholesterolemia (FH), a genetic disease characterized by elevated LDL cholesterol caused by mutations in four candidate genes: LDLR (most common), ApoB-100, PCSK9, and LDLRAP1/ARH. The paper distinguishes clinical vs. genetic nomenclature for FH diagnosis, describes genotype-phenotype correlations for each gene, and reviews clinical diagnostic criteria (MEDPED, Simon Broome, Dutch) and genetic screening programs from multiple countries showing mutation detection rates of 13-59% depending on screening strategy and methodology.

Traits studied:Familial HypercholesterolemiaHypercholesterolemiaLDL CholesterolPremature Cardiovascular Disease
PubMedDOIMetascience Observatory

Gene information from NCBI Gene. Variant classifications from ClinVar.

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