Mutations

SORL1 R1207Q

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121583497 G>A
Position: (GRCh37/hg19):Chr11:121454206 G>A
dbSNP ID: rs114830255
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 26

Findings

This variant has been found in multiple studies, in both Alzheimer’s cases and controls. Except for one study of Caribbean Hispanics, none have reported an association with AD.

The R1207Q 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 an association with Alzheimer’s disease (Vardarajan et al., 2015).

Subsequently, the R1207Q variant was reported in several case-control studies. In a European-American sample of 134 late-onset Alzheimer’s disease cases and 266 controls, the variant was found with minor allele frequencies of 3.7×10-3 and 9.4×10-3 in cases and controls, respectively (odds ratio: 0.39, p = 0.3805) (Fernández et al., 2016). This variant was also found in one of 1268 controls and none of 640 AD cases in a Dutch sample; it was not seen in a pan-European cohort of 1255 early onset AD cases and 198 controls (Holstege et al., 2017). Additionally, R1207Q was reported in four of 5198 AD cases and two 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 datasets, including ADSP and cohorts from the Dutch study cited above, this allele was observed 15 times—eight times among the AD cases and seven 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.

The R1207Q variant was classified as likely benign by the criteria of Holstege and colleagues (Holstege et al., 2017).

Functional Consequences

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

Table

Risk Allele(s) N
Cases | Controls
(families)		 aAllele frequency
Cases | Controls		 Reported association measurements Ancestry
(Cohort)		 Reference
Large-scale studies, meta- and mega-analyses  
A 15,808 | 16,097 2.53×10-4 | 2.17×10-4 OR = 0.58
[CI: 0.20-1.70]
p = 0.31		 Multiple European and American cohorts Holstege et al., 2022
(mega-analysis)
Other studies
A 852 (EOAD) | 927 (LOAD) | 1273 (CTRL) 0 | 0 | 7.86×10-4   French
(Alzheimer Disease Exome Sequencing France (ADESFR))		 Bellenguez et al., 2017; Campion et al., 2019
A 5198 | 4491 3.85×10-4 | 2.23×10-4   Non-Hispanic Caucasian
(Alzheimer’s Disease Sequencing Project (ADSP))		 Campion et al., 2019
(WES)
A sporadic LOAD
134 | 266		 3.7×10-3 | 9.4×10-3 OR = 0.39
[CI: N.A.]
p = 0.3805		 European American
(Knight ADRC, NIA-LOAD)		 Fernández et al., 2016
familial LOAD
875 | 328		 0 | 0   European American
(Knight ADRC, NIA-LOAD)
A 640 | 1268 0 | 3.94×10-4   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et al., 2017
A 332 | 676 0 | 0   UK and North American Caucasian
(NIH-UCL, Knight ADRC), ADNI, Cache County Study on Memory in Aging)		 Sassi et al., 2016; Campion et al., 2019
A 462 (87 families) |
498		 8.75×10-3 | 1.00×10-3 bp = 4.00×10-6 Caribbean Hispanic
(family- and cohort-based)		 Vardarajan et al., 2015
A 211 | 0 0 | N.A.   North European ancestry
A 1255 | 1938 0 | 0   European
(European Early Onset Dementia Consortium)		 Verheijen et al., 2016; Campion et al., 2019

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

  1. 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.
  2. Fernández MV, Black K, Carrell D, Saef B, Budde J, Deming Y, Howells B, Del-Aguila JL, Ma S, Bi C, Norton J, Chasse R, Morris J, Goate A, Cruchaga C, NIA-LOAD family study group, NCRAD. SORL1 variants across Alzheimer's disease European American cohorts. Eur J Hum Genet. 2016 Dec;24(12):1828-1830. Epub 2016 Sep 21 PubMed.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. 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.

Other mutations at this position

View Table

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.