Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121574272 T>A
Position: (GRCh37/hg19):Chr11:121444981 T>A
dbSNP ID: rs1416109745
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to TTA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 24

Findings

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, including the ADSP and ADESFR cohorts cited below, this allele was observed 20 times—eight times among the AD cases and 12 times among the controls (Holstege et al., 2022). A mega-analysis of these data did not find an association between the variant and AD risk.

Previously, the variant was reported in none of 5198 Alzheimer's cases and one of 4491 controls in a dataset from the Alzheimer’s Disease Sequencing Project (ADSP), consisting of subjects of non-Hispanic Caucasian ancestry from whom whole-exome sequencing data were available. A second carrier—a subject with AD—was found in a sample of 1779 AD cases and 1273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Campion et al., 2019).

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Phenylalanine-1123 is one of a pair of conserved hydrophobic amino acids—usually isoleucine and phenylalanine—in the N-terminal part of each CR that help to stabilize this region. Andersen and colleagues predicted that substitutions of one of these hydrophobic amino acids are moderately likely to increase AD risk (Andersen et al., 2023). However, as the F1123L variant substitutes one hydrophobic amino acid for another, it may be tolerated.

The F1123L variant was predicted to be deleterious by SIFT, Mutation Taster, and PolyPhen-2 (Campion et al., 2019).

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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. Campion D, Charbonnier C, Nicolas G. SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol. 2019 Aug;138(2):173-186. Epub 2019 Mar 25 PubMed.
3. 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