Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121558754 A>G
Position: (GRCh37/hg19):Chr11:121429463 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ATA to GTA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 20

Findings

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, this allele was observed once among the AD cases (Holstege et al., 2022).

Functional Consequences

Isoleucine-943 is found within the YWTD-repeated β-propeller domain (Andersen et al., 2023). An isoleucine is found at equivalent positions in all six blades of the YWTD-repeated β-propeller, where it is thought to help stabilize domain folding. The high conservation of isoleucine at these positions led Andersen and colleagues to predict that mutations of these residues are highly likely to increase the risk of Alzheimer’s disease. Pathogenic variants were identified in homologous positions in LDLR (linked to familial hypercholesterolemia 1) and LRP4 (found in patients with Cenani-Lenz syndactyly syndrome) (Andersen et al., 2023).

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References

Paper Citations

1. Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, van Rooij JG, Sims R, Ahmad S, Amin N, Norsworthy PJ, Dols-Icardo O, Hummerich H, Kawalia A, Amouyel P, Beecham GW, Berr C, Bis JC, Boland A, Bossù P, Bouwman F, Bras J, Campion D, Cochran JN, Daniele A, Dartigues JF, Debette S, Deleuze JF, Denning N, DeStefano AL, Farrer LA, Fernández MV, Fox NC, Galimberti D, Genin E, Gille JJ, Le Guen Y, Guerreiro R, Haines JL, Holmes C, Ikram MA, Ikram MK, Jansen IE, Kraaij R, Lathrop M, Lemstra AW, Lleó A, Luckcuck L, Mannens MM, Marshall R, Martin ER, Masullo C, Mayeux R, Mecocci P, Meggy A, Mol MO, Morgan K, Myers RM, Nacmias B, Naj AC, Napolioni V, Pasquier F, Pastor P, Pericak-Vance MA, Raybould R, Redon R, Reinders MJ, Richard AC, Riedel-Heller SG, Rivadeneira F, Rousseau S, Ryan NS, Saad S, Sanchez-Juan P, Schellenberg GD, Scheltens P, Schott JM, Seripa D, Seshadri S, Sie D, Sistermans EA, Sorbi S, van Spaendonk R, Spalletta G, Tesi N, Tijms B, Uitterlinden AG, van der Lee SJ, Visser PJ, Wagner M, Wallon D, Wang LS, Zarea A, Clarimon J, van Swieten JC, Greicius MD, Yokoyama JS, Cruchaga C, Hardy J, Ramirez A, Mead S, van der Flier WM, van Duijn CM, Williams J, Nicolas G, Bellenguez C, Lambert JC. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
2. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.

Further Reading

No Available Further Reading