Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44908851 C>T
Position: (GRCh37/hg19):Chr19:45412108 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs781722239
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CGT
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant 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 lipid deposits inside the cornea, a condition known as corneal arcus. They were 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—and their weighted polygenic risk score was low (decile II), indicating a strong probability of a single gene underlying the disease. Their APOE genotype was APOE3/E3.

The variant was found in the gnomAD variant database at a frequency of 0.00009, including 12 heterozygotes and one homozygote, all of non-Finnish European ancestry (gnomAD v3.1.1, Nov 2021).

Biological Effect

The biological effect of this variant is unknown, but computational algorithms Mutation Taster and Provean predicted it is not damaging, and its PHRED-scaled CADD score was 7.192, well below the commonly used threshold of 20 for predicting a damaging effect (Abou Khalil et al., 2022). The variant has been classified as likely benign.

Of note, a study using FRET and computational simulations to study monomeric ApoE4 predicted R185 contacts E98 in helix 2 of the N-terminal domain. This interaction was predicted to occur when ApoE is in a configuration suspected to enable lipid binding, with the C-terminal domain undocked from the N-terminal helix bundle (Stuchell-Brereton et al., 2023).

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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. Stuchell-Brereton MD, Zimmerman MI, Miller JJ, Mallimadugula UL, Incicco JJ, Roy D, Smith LG, Cubuk J, Baban B, DeKoster GT, Frieden C, Bowman GR, Soranno A. Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2215371120. Epub 2023 Feb 7 PubMed.

Further Reading

No Available Further Reading