Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44908601 C>T
Position: (GRCh37/hg19):Chr19:45411858 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs11083750
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to CTG
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—but they had a strong probability of their condition being due to variants in multiple genes (weighted polygenic risk scores in decile X). Their APOE genotype was APOE3/E4. 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 multiple computational algorithms predicted it is damaging, and its PHRED-scaled CADD score (23.4), which integrates diverse information in silico, was above 20, suggesting a deleterious effect (Abou Khalil et al., 2022). Also of note, P102 is an evolutionarily conserved amino acid and two carriers of another substitution at this position, P102R, also suffered from hypercholesterolemia. The authors classified the variant as likely pathogenic.

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References

Mutations Citations

1. APOE P102R

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