Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121470061 A>C
Position: (GRCh37/hg19):Chr11:121340770 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: AGC to CGC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 2

Findings

The S114R variant was reported in one of 1383 Alzheimer’s cases from the Centre National de Référence - Malades Alzheimer Jeunes (CNR-MAJ), the French national reference center for young Alzheimer patients (Rovelet-Lecrux et al., 2021).

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

Functional Consequences

This variant impaired maturation (glycosylation) and trafficking to the plasma membrane of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

These authors also reported that the S114R variant was predicted to be damaging by SIFT, Mutation Taster, and Polyphen-2.

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References

Paper Citations

1. Rovelet-Lecrux A, Feuillette S, Miguel L, Schramm C, Pernet S, Quenez O, Ségalas-Milazzo I, Guilhaudis L, Rousseau S, Riou G, Frébourg T, Campion D, Nicolas G, Lecourtois M. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease. Acta Neuropathol Commun. 2021 Dec 18;9(1):196. 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.

Further Reading

No Available Further Reading