Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44909286 C>G
Position: (GRCh37/hg19):Chr19:45412543 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: Exon 4, 3' UTR

Findings

This variant, located in the 3’ untranslated region of APOE mRNA, was identified in a French patient from 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 underlay the condition. They had an APOE3/E4 genotype.

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 computational algorithm Mutation Taster predicted it is not damaging, and its PHRED-scaled CADD score was 6.60, well below the commonly used threshold of 20 for predicting a damaging effect (Abou Khalil et al., 2022).

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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