Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44908999 C>T
Position: (GRCh37/hg19):Chr19:45412256 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs530010303
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to TGG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a 56-year-old man in a Norwegian cohort of 98 patients with hyperlipidemia (Marduel et al., 2013). Patients had elevated levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, and decreased levels of triglycerides in blood, typical of autosomal dominant hypercholesterolemia, also known as hyperlipoproteinemia type IIa. The man had an APOE3/E4 genotype.

The variant was absent from 500 French controls and only three European (non-Finnish) carriers were reported in the gnomAD variant database (v2.1.1, June 2022).

Biological Effect

The biological effect of this variant is unknown. An NMR study of an APOE3-like construct, suggested R235 forms a salt bridge with glutamate 68, bringing together the ApoE N- and C-termini (Chen et al., 2011). A subsequent study using FRET and computational simulations to analyze monomeric ApoE4 also identified this interaction  (Stuchell-Brereton et al., 2023). 

In silico algorithms predicted R235W is “not tolerated” (SIFT), “possibly damaging” (Polyphen), and “probably damaging” (Polyphen-2) (Marduel et al., 2013). This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, May 2022).

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References

Paper Citations

1. Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, Marques-Pinheiro A, Erik Berge K, Devillers M, Luc G, Lecerf JM, Tosolini L, Erlich D, Peloso GM, Stitziel N, Nitchké P, Jaïs JP, French Research Network on ADH, Abifadel M, Kathiresan S, Leren TP, Rabès JP, Boileau C, Varret M. Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat. 2013 Jan;34(1):83-7. Epub 2012 Oct 11 PubMed.
2. Chen J, Li Q, Wang J. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14813-8. Epub 2011 Aug 22 PubMed.
3. Stuchell-Brereton MD, Zimmerman MI, Miller JJ, Mallimadugula UL, Incicco JJ, Roy D, Smith LG, Cubuk J, Baban B, DeKoster GT, Frieden C, Bowman GR, Soranno A. Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2215371120. Epub 2023 Feb 7 PubMed.

Further Reading

No Available Further Reading