Mutations

SORL1 N1809S

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121614877 A>G
Position: (GRCh37/hg19):Chr11:121485586 A>G
dbSNP ID: rs117725215
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: AAC to AGC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 41

Findings

The N1809S variant has been found in both Alzheimer’s disease cases and in controls (Campion et al., 2019; Fernández et al., 2016; Gómez-Tortosa et al., 2018; Holstege et al., 2017; Holstege et al., 2022; Verheijen et al., 2016), and does not appear to associate with disease risk (Campion et al., 2019; Fernández et al., 2016; Holstege et al., 2022).

Within a Spanish family in which four of eight siblings were diagnosed with AD (ages of onset ranging from 72 to 78 years), the variant did not segregate with disease: Among the four individuals genotyped, the variant was found in one affected person and in two people who remained unaffected at ages 78 and 79; conversely, one of the affected siblings was a non-carrier (Gómez-Tortosa et al., 2018).

The N1809S variant is classified as likely benign by the criteria of Holstege et al. (Gómez-Tortosa et al., 2018; Holstege et al., 2017) and the guidelines of the American College of Medical Genetics and Genomics (Gómez-Tortosa et al., 2018).

Functional Consequences

The N1809S variant was predicted to be tolerated by SIFT, but deleterious by Mutation Taster and PolyPhen-2 (Campion et al., 2019).

Table

Risk Allele(s) N
Cases | Controls		 aAllele frequency
Cases | Controls		 Reported association measurements Ancestry
(Cohort)		 Reference
Large-scale studies, meta- and mega-analyses
G 9204 | 9646 1.20×10-3 | 9.85×10-4 Fixed effect model
OR = 1.13
[CI: 0.61 – 2.09]
p =  0.698
Random effects model
OR = 1.13
[CI: 0.60 – 2.10]
p = 0.705		 European, European American Campion et al., 2019
(meta-analysis)
early onset AD
3180 | 8970		 1.10×10-3 | 1.06×10-3 Fixed effect model
OR = 1.10
[CI: 0.47 – 2.59]
p = 0.83
Random effects model
OR = 1.16
[CI: 0.49 – 2.72]
p = 0.735		 European, European American
G 15,808 | 16,097 1.33×10-3 | 9.63×10-4 OR = 1.12
[CI: 0.69 – 1.82]
p = 0.65		 Multiple European and American cohorts Holstege et al., 2022
(mega-analysis)
Other studies
G 852 (EOAD) | 927 (LOAD) | 1273 (CTRL) 5.87×10-4 | 1.08×10-3 | 1.18×10-3   French
(Alzheimer Disease Exome Sequencing France (ADESFR))		 Bellenguez et al., 2017; Campion et al., 2019
G 5198 | 4491 1.54×10-3 | 1.11×10-3   Non-Hispanic Caucasian
(Alzheimer’s Disease Sequencing Project (ADSP))		 Campion et al., 2019
G sporadic EOAD
217 | 169		 2.4×10-3 | 3.1×10-3 OR = 0.766
[CI: N.A.]
p = 0.850		 European American
(Knight ADRC)		 Fernández et al., 2016
sporadic LOAD
134 | 266		 0 | 1.9×10-3 OR = 0.477
[CI: N.A.]
p = 0.5044		 European American
(Knight ADRC, NIA-LOAD)
familial LOAD
875 | 328		 1.16×10-3 | 1.54×10-3 OR = 0.748
[CI: N.A.]
p = 0.1573		 European American
(Knight ADRC, NIA-LOAD)
G 640 | 1268 0 | 4×10-4   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et al., 2017
G 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
G 1255 | 1938 2.0×10-3 | 8×10-4   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.

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. 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.
  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. Gómez-Tortosa E, Ruggiero M, Sainz MJ, Villarejo-Galende A, Prieto-Jurczynska C, Venegas Pérez B, Ordás C, Agüero P, Guerrero-López R, Pérez-Pérez J. SORL1 Variants in Familial Alzheimer's Disease. J Alzheimers Dis. 2018;61(4):1275-1281. 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.
  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. 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.
  7. 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.
  8. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. 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.
  2. Gómez-Tortosa E, Ruggiero M, Sainz MJ, Villarejo-Galende A, Prieto-Jurczynska C, Venegas Pérez B, Ordás C, Agüero P, Guerrero-López R, Pérez-Pérez J. SORL1 Variants in Familial Alzheimer's Disease. J Alzheimers Dis. 2018;61(4):1275-1281. PubMed.

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.