Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121612809 G>A
Position: (GRCh37/hg19):Chr11:121483518 G>A
dbSNP ID: rs530863434
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGA to CAA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 40

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 nine times—five times among the AD cases and four 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.

This variant was previously seen in a control subject in a data set of 927 late-onset Alzheimer’s cases, 852 early-onset cases, and 1273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Campion et al., 2019). The ADESFR contributed to the 2022 study cited above.

The R1799Q variant was also reported in a study of subjects with autopsy-confirmed Lewy body dementia (DLB), who initially had been suspected of having Creutzfeldt-Jakob's disease (CJD) due to their rapid disease course (Geut et al., 2019). The carrier was a male patient who met clinical criteria for both probable DLB and possible CJD. His APOE genotype was E2/E3, and he died at age 79. Neuropathological examination revealed moderate brain atrophy and mild spongiform changes, with evidence of small vessel disease. His pathology was described as Braak α-synuclein stage 5, McKeith Lewy body stage: transitional, Braak neurofibrillary stage 3, and Thal amyloid-β phase 1.

The R1799Q variant is classified as likely benign by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

This variant was predicted to be tolerated by SIFT, neutral by Mutation Taster, and benign by 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. Geut H, Vergouw LJ, Galis Y, Ingrassia A, de Jong FJ, Quadri M, Bonifati V, Lemstra AW, Rozemuller AJ, van de Berg WD. Neuropathological and genetic characteristics of a post-mortem series of cases with dementia with Lewy bodies clinically suspected of Creutzfeldt-Jakob's disease. Parkinsonism Relat Disord. 2019 Jun;63:162-168. Epub 2019 Feb 13 PubMed.
4. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 PubMed.

Further Reading

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