Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44908934 T>A
Position: (GRCh37/hg19):Chr19:45412191 T>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to GAG
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 cholesterol (LDL-C) in blood and was diagnosed with autosomal dominant hypercholesterolemia, also known as hyperlipoproteinemia type IIa (HLPP2a). Of note, the carrier was homozygous for a variant in the PCSK9 gene, L21dup, associated with reduced levels of LDL-C. Their APOE genotype was APOE3/E4.

The variant was absent from the gnomAD variant database.

Biological Effect

The biological effect of this variant is unknown, but the authors noted that the proband’s elevated LDL-C levels in the presence of homozygosity for an LDL-C-reducing variant argued for the pathogenicity of V213E. Predictions from multiple computational algorithms, including SIFT, Polyphen2, Mutation Taster, and Provean, were mixed. The variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was 11.3, a score which predicts the variant is in the top 10 percent of the most deleterious substitutions in the human genome. However, it did not reach the commonly used threshold of 20 corresponding to the top 1 percent of the most deleterious substitutions.

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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