Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121567110 C>G
Position: (GRCh37/hg19):Chr11:121437819 C>G
dbSNP ID: rs1699107
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CAA to GAA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 22

Findings

Note on nomenclature: The reference allele (C) at this position is the minor allele, and the alternate allele (G) is found in the vast majority of individuals. Although this variant is called “Q1074E” in the literature—and this practice will be followed here—minor allele frequencies and numbers of carriers refer to the C allele (i.e., glutamine at position 1074).

The Q1074E variant was identified in a family- and cohort-based study of Caribbean Hispanics, where joint linkage and association analysis, a method that allows researchers to analyze together data from families and unrelated subjects, showed that the C allele associated with Alzheimer’s disease (Vardarajan et al., 2015).

Subsequently, this variant was found in one of 1255 AD cases and one of 1938 controls in a pan-European study from the European Early-Onset Dementia Consortium (Verheijen et al., 2016), one of 676 controls and none of 332 AD cases in a Caucasian cohort from Britain and North America (Sassi et al., 2016), and two of 5198 cases and none 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 (Campion et al., 2019).

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).

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

Functional Consequences

The Q1074E variant was predicted to be benign by PolyPhen-2, tolerated by SIFT, and was classified as a polymorphism by Mutation Taster (Campion et al., 2019).

Table

Risk Allele(s)	N Cases (families)\| Controls	^aAllele frequency Cases \| Controls	Reported association measurements	Ancestry (Cohort)	Reference(s)
Large-scale studies, meta- and mega-analyses
C	15,808 \| 16,097	6.33×10^-5 \| 0		Multiple European and American cohorts	Holstege et al., 2022 (mega-analysis)
Other studies
C	852 (EOAD) \| 927 (LOAD) \| 1273 (CTRL)	0 \| 0 \| 0		French (Alzheimer Disease Exome Sequencing France (ADESFR))	Bellenguez et al., 2017; Campion et al., 2019
C	5198 \| 4491	1.92×10^-4 \| 0		Non-Hispanic Caucasian (Alzheimer’s Disease Sequencing Project (ADSP))	Campion et al., 2019
C	640 \| 1268	0 \| 0		Dutch (Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)	Holstege et al., 2017
C	332 \| 676	0 \| 7.4×10^-4	OR = 0 [CI: 0 – 79.31] p = 1	UK and North American Caucasian (NIH-UCL, Knight ADRC, ADNI, Cache County Study on Memory in Aging)	Sassi et al., 2016
C	462 (87)\| 498	2.77×10^-2 \| 1.91×10^-2	^bp = 1.41×10^-10	Caribbean Hispanic [family- and cohort-based]	Vardarajan et al., 2015
C	1255 \| 1938	3.98×10^-4\| 2.58×10^-4		European (European Early-Onset Dementia Consortium)	Verheijen et al., 2016

^aAllele frequencies as reported by study authors or calculated by Alzforum curators from data provided in the study, assuming heterozygosity if not explicitly stated in the paper.
^bLinkage and association analysis with PSEUDOMARKER using all family members and unrelated controls

This table is meant to convey the range of results reported in the literature. As specific analyses, including co-variates, differ among studies, this information is not intended to be used for quantitative comparisons, and readers are encouraged to refer to the original papers. Thresholds for statistical significance were defined by the authors of each study. (Significant results are in bold.) Note that data from some cohorts may have contributed to multiple studies, so each row does not necessarily represent an independent dataset. While every effort was made to be accurate, readers should confirm any values that are critical for their applications.

Last Updated: 18 Jul 2024

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, Reitz C, Reyes-Dumeyer D, Shen Y, Rogaeva E, St George-Hyslop P, Mayeux R. Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015 Feb;77(2):215-27. PubMed.
Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S, Pastor MA, Benussi L, Ghidoni R, Binetti G, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Grau-Rivera O, Gelpi E, Bettens K, Mateiu L, Dillen L, Cras P, De Deyn PP, Van Broeckhoven C, Sleegers K. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):213-24. Epub 2016 Mar 30 PubMed.
Sassi C, Ridge PG, Nalls MA, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, ARUK Consortium, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Bras J, Goate AM, Singleton AB, Guerreiro R, Hardy J. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease. PLoS One. 2016;11(6):e0150079. Epub 2016 Jun 1 PubMed.
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.
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.
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.
Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, Chauhan G, Wallon D, Rousseau S, Richard AC, Boland A, Bourque G, Munter HM, Olaso R, Meyer V, Rollin-Sillaire A, Pasquier F, Letenneur L, Redon R, Dartigues JF, Tzourio C, Frebourg T, Lathrop M, Deleuze JF, Hannequin D, Genin E, Amouyel P, Debette S, Lambert JC, Campion D, CNR MAJ collaborators. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging. 2017 Nov;59:220.e1-220.e9. Epub 2017 Jul 14 PubMed.

Mutations

SORL1 Q1074E

Quick Links