Overview

Clinical Phenotype: Hyperlipoproteinemia Type III
Position: (GRCh38/hg38):Chr19:44908500 C>G
Position: (GRCh37/hg19):Chr19:45411757 C>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Intron 3

Findings

Although this variant is intronic, it was reported in a study in which Exon 4 of the APOE gene was sequenced in samples of more than 4,000 Spanish individuals, including patients from a lipid clinic and volunteers from the Aragon Workers Health study (Bea et al., 2023). The variant was identified in an APOE2 homozygote patient who fulfilled the criteria for dysbetalipoproteinemia, also known as hyperlipoproteinemia type III (HLPP3). This condition is characterized by early onset atherosclerosis and heart disease and is most often associated with APOE2 homozygosity. In this study, two ratios were used for diagnosis: cholesterol other than that in high-density lipoprotein (non-HDLc)/ApoB≥1.7 and triglycerides/ApoB≥1.35.

Analysis of first-degree relatives of index cases revealed three additional carriers, including another APOE2 homozygote and two APOE2 heterozygotes (APOE3/E2 and APOE4/E2). Importantly, only the APOE2 homozygotes, both near age 40, had HLPP3, while the heterozygotes, 49 and 68 years old, did not. As noted by the authors, it is thus uncertain if c.237-33C>G on its own is tied to any alteration of lipid metabolism. (None of the carriers, including the APOE2 homozygotes, had atherosclerotic cardiovascular disease at the time of the study.)

The variant was absent from both the gnomAD and 1000 Genomes Project databases.

Biological Effect
The biological effect of this variant is unknown, but it was predicted to be neutral by the in silico algorithm PredictSNP2 (Bea et al., 2023). Moreover, its PHRED-scaled CADD score (11.42) was below 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

No Available Further Reading