Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIb
Position: (GRCh38/hg38):Chr19:44906678 G>A
Position: (GRCh37/hg19):Chr19:45409935 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs770658351
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Intron 2

Findings

This variant, located 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 X), indicating a strong probability that multiple genes underlie the condition. Their APOE genotype was APOE3/E4.

The variant was absent from the gnomAD variant database (gnomAD v3.1.1, Nov 2021).

Biological Effect

The biological effect of this variant is unknown, but the computational algorithm Mutation Taster predicted it is benign and its PHRED-scaled CADD score was 13.12, predicted to be 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.

Further Reading

No Available Further Reading