Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44907759 G>C
Position: (GRCh37/hg19):Chr19:45411016 G>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion
Reference Isoform: APOE Isoform 1
Genomic Region: Intron 2

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 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—and their weighted polygenic risk score was low (decile II), indicating a strong probability of the disease being due to a single gene. 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 it is predicted to destroy the intron 2 acceptor splice site which could lead to skipping of exon 2 or other splicing alterations (Abou Khalil et al., 2022). Consistently, the computational algorithm Mutation Taster predicted it is disease-causing, and its PHRED-scaled CADD score (33), which integrates diverse information in silico, was well above 20, suggesting a deleterious effect.

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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