Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44908858 G>T
Position: (GRCh37/hg19):Chr19:45412125 G>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to TGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was reported in a 56-year-old Spanish patient with hypercholesterolemia (Bea et al., 2023). It was identified after sequencing of Exon 4 of the APOE gene. No known pathogenic mutations were found in genes associated with familial hypercholesterolemia (a.k.a., hyperlipoproteinemia type 2a), including LDLR, APOB and PCSK9. The carrier was homozygous for the APOE3 allele. None of the carrier’s relatives who were analyzed in this study had hypercholesterolemia nor carried the mutation.

This variant was absent from the gnomAD and the 1000 Genomes Project variant databases.

Biological Effect
The mutant protein had reduced affinity for low-density lipoprotein (LDL) receptors compared with wildtype ApoE3 (Bea et al., 2023).  Affinity was assessed by in vitro binding assays using the LDL receptor ectodomain attached to plates exposed to VLDL particles isolated from the patient.

The Polyphen2 algorithm predicted the variant is probably damaging, and its PHRED-scaled CADD score, which integrates multiple factors in silico, was 22.4, clearing the commonly used deleteriousness threshold of 20 (v1.6, July 2023). However, other algorithms used to predict deleteriousness yielded inconsistent results.

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References

Paper Citations

1. 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