Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44908759 C>T
Position: (GRCh37/hg19):Chr19:45412016 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs1018669382
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to TTC
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, aka hyperlipoproteinemia type IIa (HLPP2a). They did not carry mutations in the genes most commonly associated with HLPP1, LDLR, PCSK9, or APOB. Their APOE genotype was APOE3/E3.

The authors noted the frequency of the variant in the cohort was greater (0.00009) than in the gnomAD variant database (0.00001, gnomAD v3.1.1, Nov 2021), prompting them to classify the variant as likely pathogenic. However, note that the cohort frequency is based on the presence of a single carrier.

Biological Effect

The biological effect of this variant is unknown, but multiple computational algorithms predicted it is benign and its PHRED-scaled CADD score (5.538), which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (Abou Khalil et al., 2022).

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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