Mutations

SORL1 D140N

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121478133 G>A
Position: (GRCh37/hg19):Chr11:121348842 G>A
dbSNP ID: rs140888526
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 3

Findings

The D140N variant was identified in both Alzheimer’s cases and controls in multiple studies, some of which drew from the same datasets. The variant did not associate with AD risk in the studies in which association was tested statistically.

This variant was also found in an individual clinically diagnosed with rapidly progressing Lewy body disease (Geut et al., 2019). At autopsy, this patient was found to exhibit Alzheimer’s pathology and cerebral amyloid angiopathy, in addition to Lewy body pathology. His APOE genotype was E3/E4.

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

Functional Consequences

Aspartate-140 is part of a conserved motif within the propellers of the VPS10P domain called the “Asp-box.” While the function of this motif is not known, it has been suggested that it stabilizes the propeller. Andersen and colleagues have predicted that mutations at this position are highly likely to associate with AD risk (Andersen et al., 2023). However, it should be noted that, among 40 species examined, an asparagine occurred at the homologous position in two cases.

The aspartate-to-asparagine substitution at amino acid 140 was predicted to be probably damaging by PolyPhen-2, tolerated by SIFT, and disease-causing by Mutation Taster (Sassi et al., 2016).

In a study investigating the effects of SORL1 missense mutations on protein processing, this variant did not affect the maturation (glycosylation) or trafficking to the plasma membrane of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021).

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 8.22×10-4 | 5.59×10-4 OR = 1.48
[CI: 0.78-2.78]
p = 0.23		 Multiple European and American cohorts Holstege et al., 2022
(mega-analysis)
Other studies
A 852 (EOAD) | 927 (LOAD) | 1273 (CTRL) 5.87×10-4 | 5.39×10-4 | 3.93×10-4   French
(Alzheimer Disease Exome Sequencing France (ADESFR))		 Bellenguez et al., 2017, Campion et al., 2019
A 5740 | 5096   Not significantly associated with AD risk European, Caribbean Hispanic
(Alzheimer’s Disease Sequencing Project (ADSP))		 Bis et al., 2018
(WES)
A 5198 | 4491 1.25×10-3 | 3.34×10-4   Non-Hispanic Caucasian
(ADSP)		 Campion et al., 2019
A sporadic EOAD
217 | 169		 0 | 0   European American
(Knight ADRC)		 Fernández et al., 2016
familial LOAD
875 | 328		 0 | 1.52×10-3 p = 0.1336 European American
(Knight ADRC, NIA-LOAD)
A 640 | 1268 0 | 7.89×10-4   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et al., 2017
A 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
A 1255 | 1938 4×10-4 | 2.6×10-4   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

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References

Paper Citations

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. Bis JC, Jian X, Kunkle BW, Chen Y, Hamilton-Nelson KL, Bush WS, Salerno WJ, Lancour D, Ma Y, Renton AE, Marcora E, Farrell JJ, Zhao Y, Qu L, Ahmad S, Amin N, Amouyel P, Beecham GW, Below JE, Campion D, Charbonnier C, Chung J, Crane PK, Cruchaga C, Cupples LA, Dartigues JF, Debette S, Deleuze JF, Fulton L, Gabriel SB, Genin E, Gibbs RA, Goate A, Grenier-Boley B, Gupta N, Haines JL, Havulinna AS, Helisalmi S, Hiltunen M, Howrigan DP, Ikram MA, Kaprio J, Konrad J, Kuzma A, Lander ES, Lathrop M, Lehtimäki T, Lin H, Mattila K, Mayeux R, Muzny DM, Nasser W, Neale B, Nho K, Nicolas G, Patel D, Pericak-Vance MA, Perola M, Psaty BM, Quenez O, Rajabli F, Redon R, Reitz C, Remes AM, Salomaa V, Sarnowski C, Schmidt H, Schmidt M, Schmidt R, Soininen H, Thornton TA, Tosto G, Tzourio C, van der Lee SJ, van Duijn CM, Vardarajan B, Wang W, Wijsman E, Wilson RK, Witten D, Worley KC, Zhang X, Alzheimer’s Disease Sequencing Project, Bellenguez C, Lambert JC, Kurki MI, Palotie A, Daly M, Boerwinkle E, Lunetta KL, Destefano AL, Dupuis J, Martin ER, Schellenberg GD, Seshadri S, Naj AC, Fornage M, Farrer LA. Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. Mol Psychiatry. 2018 Aug 14; PubMed.
  7. 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.
  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.
  9. 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.
  10. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.
  11. Rovelet-Lecrux A, Feuillette S, Miguel L, Schramm C, Pernet S, Quenez O, Ségalas-Milazzo I, Guilhaudis L, Rousseau S, Riou G, Frébourg T, Campion D, Nicolas G, Lecourtois M. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease. Acta Neuropathol Commun. 2021 Dec 18;9(1):196. 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. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.

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