Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Reference Assembly: GRCh37/hg19
Position: Chr19:45411963 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs11542035
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
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 (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. Their APOE genotype was APOE3/E3.

The variant was found in the gnomAD variant database at a frequency of 0.00003, including five heterozygotes, four of European ancestry and one of African ancestry (gnomAD v3.1.1, Nov 2021).

Biological Effect

The biological effect of this variant is unknown, but R137 lies within the receptor-binding region of ApoE. Three computational algorithms, SIFT, Mutation Taster, and Provean predicted R137C is not damaging, but SIFT predicted a deleterious effect (Abou Khalil et al., 2022). The variant’s PHRED-scaled CADD score was 22.1, above the commonly used threshold of 20 for predicting a damaging 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