Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44905784 G>A
Position: (GRCh37/hg19):Chr19:45409041 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs766215051
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 1, 5' UTR

Findings

This variant, located in the APOE promoter and in the 5’ untranslated region of APOE mRNA, was identified in a French patient in a cohort of nearly 6,000 unrelated individuals with primary dyslipidemia (Abou Khalil et al., 2022). The carrier had elevated low-density lipoprotein (LDL) cholesterol in blood and was diagnosed with autosomal dominant hypercholesterolemia, also known as hyperlipoproteinemia type IIa (HLPP2a). They did not carry mutations in the genes most commonly associated with HLPP2a—LDLR, PCSK9, APOB—but their weighted polygenic risk score was high (decile IX), indicating a strong probability that multiple genes underlie the condition. Their APOE genotype was APOE3/E4.

The variant was found at a frequency of 0.00003 in the gnomAD variant database, including five heterozygotes of different ancestries (gnomAD v3.1.1, Nov 2021).

Biological Effect

The biological effect of this variant is unknown, but it is in the APOE promoter (Paik et al., 1988) within the HuB functional domain (-101 to -15) which was identified as a positive regulatory element and possibly forming part of the core promoter site for transcription initiation (Maloney et al., 2007).

The computational algorithm Mutation Taster predicted this variant is disease-causing and its PHRED-scaled CADD score was 14.13, suggesting it is among the top 10 percent of the most deleterious substitutions in the human genome (Abou Khalil et al., 2022). Note, however, that a score of 20 (corresponding to the top 1 percent) is commonly used as a threshold for predicting a damaging effect.

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References

Paper Citations

1. Abou Khalil Y, Marmontel O, Ferrières J, Paillard F, Yelnik C, Carreau V, Charrière S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrié A, Rabès JP, Varret M. APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci. 2022 May 21;23(10) PubMed.
2. Paik YK, Chang DJ, Reardon CA, Walker MD, Taxman E, Taylor JM. Identification and characterization of transcriptional regulatory regions associated with expression of the human apolipoprotein E gene. J Biol Chem. 1988 Sep 15;263(26):13340-9. PubMed.
3. Maloney B, Ge YW, Alley GM, Lahiri DK. Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer's disease. J Neurochem. 2007 Nov;103(3):1237-57. PubMed.

Further Reading

No Available Further Reading