Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121496945 C>T
Position: (GRCh37/hg19):Chr11:121367654 C>T
dbSNP ID: rs1292268635
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Nonsense
Codon Change: CGA to TGA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 6

Findings

In a whole-exome sequencing study of more than 20,000 individuals (6,965 Alzheimer’s disease cases and 13,232 controls) from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer’s Disease Sequencing Project, and the Institute of Genomic Medicine at Columbia University, this protein-truncating variant was found in a single subject—a non-Hispanic white woman with autopsy-confirmed Alzheimer’s disease (Braak stage 6) (Raghavan et al., 2018).

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

Functional Consequences

The variant is predicted to be disease-causing by Mutation Taster (Campion et al., 2019).

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References

Paper Citations

1. Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, Wolock CJ, Kamalakaran S, Petrovski S, Tosto G, Vardarajan BN, Goldstein DB, Mayeux R, Alzheimer's Disease Sequencing Project. Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol. 2018 Jul;5(7):832-842. Epub 2018 May 24 PubMed.
2. 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.
3. 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.

Further Reading

No Available Further Reading