Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type IIb
Position: (GRCh38/hg38):Chr19:44908955 C>T
Position: (GRCh37/hg19):Chr19:45412212 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs1265743589
Coding/Non-Coding: Coding
Codon Change: CCG to CTG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a Spanish patient with combined hyperlipidemia (Bea et al., 2023). The study included more than 4,000 Spanish individuals, including patients from a lipid clinic and control volunteers from the Aragon Workers Health study. The variant was identified after sequencing of Exon 4 of the APOE gene.

After genotyping relatives from index patients, the variant was found in two additional individuals. All carriers were APOE3 homozygotes. Mean concentrations of both cholesterol and triglycerides were elevated. The lipoprotein profiles of individual carriers varied, with levels of some particles in the normal range. None of the carriers fulfilled the criteria for dysbetalipoproteinemia, a.k.a. hyperlipoproteinemia type III, a condition associated with APOE2 homozygosity and other APOE mutations.

Two heterozygotes of European ancestry were reported in the gnomAD variant database, with a global frequency of 0.000013 (v2.1.1, July 2023). The variant was absent from the 1000 Genomes Project (Bea et al., 2023).

Biological Effect
The mutant protein had increased affinity for low-density lipoprotein (LDL) receptors compared with wildtype ApoE3 (Bea et al., 2023).  Affinity was assessed by in vitro binding assays using the LDL receptor ectodomain attached to plates exposed to VLDL particles isolated from carriers.

At least three of four in silico algorithms predicted the variant is deleterious. Moreover, its PHRED-scaled CADD score which integrates multiple types of in silico data was 22.4, above the commonly used threshold of 20 to assess deleteriousness (v1.6, July 2023).

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References

Paper Citations

1. Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C, Cenarro A. Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol. 2023 Jun;43(6):1066-1077. Epub 2023 Apr 13 PubMed.

Further Reading

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