Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44908545 C>T
Position: (GRCh37/hg19):Chr19:45411802 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs767980905
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to GAT
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

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

The variant was found in the gnomAD variant database at a frequency of 0.00003, including four heterozygotes, three of whom were of European ancestry (gnomAD v3.1.1, Nov 2021).

Biological Effect

The biological effect of this variant is unknown. Although the computational algorithm Mutation Taster predicted it is disease-causing, Provean predicted it was neutral (Abou Khalil et al., 2022). Moreover, its PHRED-scaled CADD score was 0.615, well below 20, the commonly used threshold for predicting a damaging effect.

Of note, a study using FRET and computational simulations to study monomeric ApoE4 predicted D83 contacts R209 and V208 in the ApoE hinge domain. These interactions were 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