Mutations

SORL1 D734N

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121550604 G>A
Position: (GRCh37/hg19):Chr11:121421313 G>A
dbSNP ID: rs148430425
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to AAC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 16

Findings

The D734N variant has been found in Europeans and Americans of European ancestry, in both Alzheimer’s patients and controls, and does not appear to associate with AD.

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 28 times—18 times among the AD cases and 10 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. Nor did a meta-analysis of more than 18,000 subjects of European ancestry (Campion et al., 2019). There is some overlap between the cohorts analyzed in these two studies.

This variant is classified as “uncertain: most likely not pathogenic” by the criteria of Holstege et al. (Holstege et al., 2017) and as likely benign by the criteria of the American College of Medical Genetics and Genomics (Thonberg et al., 2017).

Functional Consequences

The variant is predicted to be deleterious by SIFT, disease-causing by Mutation Taster, and probably damaging by PolyPhen-2 (Sassi et al., 2016).

Table

Risk Allele(s) N
Cases | Controls		 aAllele frequency
Cases | Controls		 Reported association measurements Ancestry
(Cohort)		 Reference(s)
Large-scale studies, meta- and mega-analyses
A 9204 | 9646 9.24×10-4 | 5.18×10-4 Fixed effect model
OR = 1.97
[CI: 0.90 – 4.31]
p = 0.092
Random effects model
OR = 1.95
[CI: 0.86 – 4.41]
p = 0.112		 European, European American Campion et al., 2019
(meta-analysis)
early onset AD
3180| 8970		 9.43×10-4 | 5.57×10-4 Fixed effect model
OR = 1.43
[CI: 0.53 – 3.88]
p = 0.486
Random effects model
OR = 1.60
[CI: 0.57 – 4.54]
p = 0.374		 European, European American
A 15,808 | 16,097 5.69×10-4 | 3.11×10-4 OR = 1.77
[CI: 0.81– 3.87]
p = 0.16		 Multiple European and American cohorts Holstege et al., 2022
(mega-analysis)
Other studies
A 852 (EOAD) | 927 (LOAD) | 1273 (CTRL) 0 | 2.16×10-3 | 7.86×10-4   French
(Alzheimer Disease Exome Sequencing France (ADESFR))		 Bellenguez et al, 2017; Campion et al., 2019
A 5198 | 4491 6.7×10-4 | 2.23×10-4   Non-Hispanic Caucasian
(Alzheimer’s Disease Sequencing Project (ADSP))		 Campion et al., 2019
A sporadic EOAD
217 | 169		 0 | 0   European American
(Knight ADRC)		 Fernández et al., 2016
familial LOAD
875 | 328		 2.89×10-3 | 0 p = 0.3173 European American
(Knight ADRC, NIA-LOAD)
A 640 | 1268 7.8 ×10-4 | 1.18×10-3   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et al., 2017
A 332 | 676 1.5×10-3 | 0 OR = Inf
[CI: 0.052-Inf]
p = 0.3294		 UK and North American Caucasian
(NIH-UCL, Knight ADRC, ADNI, Cache County Study on Memory in Aging)		 Sassi et al., 2016
A 183 | 303 1.09×10-2 | 5.0×10-3   Swedish
(European Early-Onset Dementia Consortium)		 bThonberg et al., 2017
A 1255 | 1938 1.6×10-3 | 7.7×10-4   European
(European Early-Onset Dementia Consortium)		 bVerheijen 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.
bSame carriers reported by Thonberg et al. and Verheijen et al.

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

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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. 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. Thonberg H, Chiang HH, Lilius L, Forsell C, Lindström AK, Johansson C, Björkström J, Thordardottir S, Sleegers K, Van Broeckhoven C, Rönnbäck A, Graff C. Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene. Acta Neuropathol Commun. 2017 Jun 9;5(1):43. PubMed.
  5. 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.
  6. 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.
  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. 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.

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