Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44908705 C>T
Position: (GRCh37/hg19):Chr19:45411962 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs573658040
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
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/E4.

The variant was found in the gnomAD variant database at a frequency of 0.00002, including three heterozygotes, two of European ancestry and one of South Asian 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. Moreover, one study suggested this residue may help stabilize the V-shaped configuration of ApoE4 dimers which is distinct from that of T-shaped ApoE2 and ApoE3 dimers and more aggregate-prone (Nemergut et al., 2023).

Although the computational algorithms Polyphen2 and Mutation Taster predicted R137C is damaging, Provean and SIFT predicted it was not (Abou Khalil et al., 2022). The variant’s PHRED-scaled CADD score was 25.8, 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.
2. Nemergut M, Marques SM, Uhrik L, Vanova T, Nezvedova M, Gadara DC, Jha D, Tulis J, Novakova V, Planas-Iglesias J, Kunka A, Legrand A, Hribkova H, Pospisilova V, Sedmik J, Raska J, Prokop Z, Damborsky J, Bohaciakova D, Spacil Z, Hernychova L, Bednar D, Marek M. Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate. Mol Neurodegener. 2023 Jun 6;18(1):38. PubMed.

Further Reading

No Available Further Reading