Overview

Clinical Phenotype: Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44909171 G>A
Position: (GRCh37/hg19):Chr19:45412428 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs121918398
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 rare variant was found in an individual from a randomly collected population of healthy 35-year-old Dutch men (van den Maagdenberg et al., 1993, Smit et al., 1988). At age 40, the proband was described as being normolipidemic and having a normal lipoprotein profile in blood, although his total cholesterol levels (5.7 mmol/L) were slightly above the normal range (van den Maagdenberg et al., 1993).

Isoelectric focusing of his ApoE protein resulted in two bands: one corresponding to the common ApoE3 allele and a second migrating to a slightly more cathodic position than C130R (ApoE4). DNA sequencing revealed a wildtype APOE3 allele and an APOE4 allele with an additional nucleotide change resulting in the R292H variant. The mutation was also found in the proband’s 76-year-old mother and three of his four sisters. Except for one of the sisters, all carriers had moderately elevated cholesterol. Of note, the proband’s father, a non-carrier, had higher levels of cholesterol than any of the other members examined, as well as elevated triglycerides. All carriers had normal triglyceride levels. 

A single European (non-Finnish) heterozygote was reported in the gnomAD variant database (v2.1.1, Oct 2022). The variant’s global frequency was 0.0000045.

Biological Effect

The biological effect of this variant is unknown, but its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (25.3) suggesting a deleterious effect (CADD v.1.6, Oct 2022).

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References

Paper Citations

1. van den Maagdenberg AM, Weng W, de Bruijn IH, de Knijff P, Funke H, Smelt AH, Gevers Leuven JA, van't Hooft FM, Assmann G, Hofker MH. Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet. 1993 May;52(5):937-46. PubMed.
2. Smit M, de Knijff P, Rosseneu M, Bury J, Klasen E, Frants R, Havekes L. Apolipoprotein E polymorphism in The Netherlands and its effect on plasma lipid and apolipoprotein levels. Hum Genet. 1988 Nov;80(3):287-92. PubMed.

Further Reading

No Available Further Reading