Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44909102 G>A
Position: (GRCh37/hg19):Chr19:45412359 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
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 variant was found in a Qatari individual diagnosed with familial hypercholesterolemia, also known as hyperlipoproteinemia type IIa (HLPP2a), a disorder characterized by elevated low-density lipoprotein cholesterol in blood and an increased risk of atherosclerosis and early onset coronary heart disease (Diboun et al., 2022). The individual was a participant in the population-based Qatar Biobank study. The variant was identified by whole-genome sequencing after filtering for variants with minor allele frequencies under 0.005, a threshold corresponding to an estimated HLPP2a prevalence of approximately 1 in 200. The variant was absent from the gnomAD variant database.

Of note, another substitution at this position, R269G, was identified as protective for Alzheimer’s disease (June 2022 news, Le Guen et al., 2022).

Biological Effect

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

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References

Mutations Citations

1. APOE R269G

News Citations

1. Two ApoE Mutations Decrease Risk for Alzheimer's Disease 10 Jun 2022

Paper Citations

1. Diboun I, Al-Sarraj Y, Toor SM, Mohammed S, Qureshi N, Al Hail MS, Jayyousi A, Al Suwaidi J, Albagha OM. The Prevalence and Genetic Spectrum of Familial Hypercholesterolemia in Qatar Based on Whole Genome Sequencing of 14,000 Subjects. Front Genet. 2022;13:927504. Epub 2022 Jul 15 PubMed.
2. Le Guen Y, Belloy ME, Grenier-Boley B, de Rojas I, Castillo-Morales A, Jansen I, Nicolas A, Bellenguez C, Dalmasso C, Küçükali F, Eger SJ, Rasmussen KL, Thomassen JQ, Deleuze JF, He Z, Napolioni V, Amouyel P, Jessen F, Kehoe PG, van Duijn C, Tsolaki M, Sánchez-Juan P, Sleegers K, Ingelsson M, Rossi G, Hiltunen M, Sims R, van der Flier WM, Ramirez A, Andreassen OA, Frikke-Schmidt R, Williams J, Ruiz A, Lambert JC, Greicius MD, Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups, Arosio B, Benussi L, Boland A, Borroni B, Caffarra P, Daian D, Daniele A, Debette S, Dufouil C, Düzel E, Galimberti D, Giedraitis V, Grimmer T, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jürgen D, Kuulasmaa T, van der Lugt A, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Moebus S, Nacmias B, Nicolas G, Olaso R, Papenberg G, Parnetti L, Pasquier F, Peters O, Pijnenburg YA, Popp J, Rainero I, Ramakers I, Riedel-Heller S, Scarmeas N, Scheltens P, Scherbaum N, Schneider A, Seripa D, Soininen H, Solfrizzi V, Spalletta G, Squassina A, van Swieten J, Tegos TJ, Tremolizzo L, Verhey F, Vyhnalek M, Wiltfang J, Boada M, García-González P, Puerta R, Real LM, Álvarez V, Bullido MJ, Clarimon J, García-Alberca JM, Mir P, Moreno F, Pastor P, Piñol-Ripoll G, Molina-Porcel L, Pérez-Tur J, Rodríguez-Rodríguez E, Royo JL, Sánchez-Valle R, Dichgans M, Rujescu D. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease. JAMA Neurol. 2022 Jul 1;79(7):652-663. PubMed.

Further Reading

No Available Further Reading