Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type IIb, Hyperlipoproteinemia Type III
Position: (GRCh38/hg38):Chr19:44908947 C>T
Position: (GRCh37/hg19):Chr19:45412204 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs72654468
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to GCT
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant has been identified in at least 17 European individuals, including both healthy controls and patients with blood lipid abnormalities.

It was first reported in three unrelated French patients in a cohort of nearly 6,000 unrelated individuals with primary dyslipidemia (Abou Khalil et al., 2022). The carriers had elevated low-density lipoprotein (LDL) cholesterol in blood and 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 scores were high (deciles VIII-X), indicating a strong probability of multiple genes underlying their condition. They were all APOE3 homozygotes.

A subsequent study identified 14 Spanish carriers, including six with hypercholesterolemia, three with combined hyperlipidemia (one of whom fulfilled the criteria for hyperlipoproteinemia type III), one with a normal lipid profile, and four ostensibly healthy volunteers from a control group (Bea et al., 2023). Except for one carrier who had an APOE3/E4 genotype, all others were APOE3 homozygotes.

The variant was found in the gnomAD variant database at a frequency of 0.0009, including 135 heterozygotes, most of non-Finnish European ancestry (gnomAD v3.1.1, Nov 2021). It was also found at a similar frequency in the 1000 Genomes Project (Bea et al., 2023).

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 was classified as likely benign by these authors and ClinVar classifications included benign and without clinical significance (Bea 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. Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C, Cenarro A. Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol. 2023 Jun;43(6):1066-1077. Epub 2023 Apr 13 PubMed.

Further Reading

No Available Further Reading