Mutations

SORL1 D2065V

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121625107 A>T
Position: (GRCh37/hg19):Chr11:121495816 A>T
dbSNP ID: rs140327834
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAT to GTT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 46

Findings

The D2065V variant has been found in both Alzheimer’s cases and controls in multiple studies of people of European descent (Fernández et al., 2016; Nicolas et al., 2016; Nicolas et al., 2018; Sassi et al., 2016; Vardarajan et al., 2015; Verheijen et al., 2016). The variant did not associate with disease in the four cohorts in two studies in which association was tested statistically (Fernández et al., 2016; Sassi et al., 2016). Nor did it associate with AD in a meta-analysis of five studies including more than 18,000 subjects of European or European American ancestry (Campion et al., 2019) or a mega-analysis of nearly 32,000 subjects from multiple European and American datasets (Holstege et al., 2022). The lack of association persisted when the latter dataset was expanded to more than 40,000 subjects (Holstege et al., 2023).

In a Spanish family with a history of AD, the variant did not segregate with disease: Of the three affected siblings who were genotyped, two carried the mutation, but one did not (Gómez-Tortosa et al., 2018).

The D2065V variant is classified as likely benign by the criteria of Holstege et al. (Holstege et al., 2017) and by the American College of Medical Genetics and Genomics guidelines (Gómez-Tortosa et al., 2018).

Functional Consequences

Two studies reported that the aspartate-to-valine substitution was predicted to be tolerated by SIFT, probably damaging by PolyPhen, and disease causing by Mutation Taster (Campion et al., 2019; Sassi et al., 2016), while two other studies reported that all three tools predicted that the variant would be damaging (Nicolas et al., 2016; Nicolas et al., 2018). gnomAD reported that SIFT predicted the variant is deleterious and PolyPhen called it probably damaging (searched May 19, 2023).

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

Table

Risk Allele(s) N
Cases | Controls		 aAllele frequency
Cases | Controls		 Reported association measurements Ancestry
(Cohort)		 Reference
Large-scale studies, meta- and mega-analyses
T 9204 | 9646 4.02×10-3 | 3.21×10-3 Fixed effect model
OR = 1.21
[CI: 0.86 – 1.71]
p = 0.277
Random effects model
OR = 1.27
[CI: 0.88 – 1.82]
p = 0.2		 European, European American Campion et al., 2019
(meta-analysis)
early onset AD
3180 | 8970		 3.62×10-3 | 3.07×10-3 Fixed effect model
OR = 1.33
[CI: 0.80 – 2.21]
p = 0.273
Random effects model
OR = 1.33
[CI: 0.80 – 2.21]
p = 0.27
T 15,808 | 16,097 4.81×10-3 | 5.53×10-3 OR = 1.01
[CI: 0.80 – 1.27]
p = 0.93		 Multiple European and American cohorts Holstege et al., 2022
(mega-analysis)
T 18,959 | 21,893   OR = 0.9
[CI: 0.7 – 1.07]
p = 0.179		 bMultiple European and American cohorts Holstege et al., 2023
early onset AD
6,154 | 21,893		   OR = 0.87
[CI: 0.64 – 1.18]
p = 0.37
late-onset AD
12,805 | 21,893		   OR = 0.9
[CI: 0.68 – 1.09]
p = 0.22
Other studies
T 852 (EOAD) | 927 (LOAD) | 1273 (CTRL) 7.04×10-3 | 5.39×10-3 | 5.50×10-3   French
(Alzheimer Disease Exome Sequencing France (ADESFR))		 Bellenguez et al., 2017;
Campion et al., 2019
T  5198 | 4491 3.85×10-3 | 3.01×10-3   Non-Hispanic Caucasian
(Alzheimer’s Disease Sequencing Project (ADSP))		 Campion et al., 2019
A sporadic EOAD
217 | 169 		  4.7×10-3 | 3×10-3 OR = 1.559
[CI: N.A.]
p = 0.715		 European American
(Knight ADRC)		  Fernández et al., 2016
A sporadic LOAD
134 | 266		 0 | 1.9×10-3 OR = 0
[CI: N.A.]
p = 0.4776		 European American
(Knight ADRC, NIA-LOAD)
T familial LOAD
876 | 328		 2.31×10-3 | 0 p = 0.9813 European American
(Knight ADRC, NIA-LOAD)
T fEOAD | fLOAD | CTRL
44 | 80 | 200		 2.27×10-2 | 0 | 0   Spanish
(Memory clinic of Fundación Jiménez Díaz,
Madrid)		 Gómez-Tortosa et al., 2018
T 640 | 1268 9.38 ×10-3 | 5.52×10-3   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et al., 2017
T early onset AD
484 | 498		 6.2×10-3 | 6.2×10-3   French
(CNR-MAJ)		 Nicolas et al., 2016
T 332 | 676 0 | 5.2×10-3 OR = 0
[CI = 0 – 1.407]
p = 0.102		 UK and North American
Caucasian
(NIH-UCL, Knight ADRC, ADNI, Cache County Study on Memory in Aging)		 Sassi et al., 2016
T 211 | 0 5×10-3 | N.A.   North European Vardarajan et al., 2015 
T 1255 | 1938 4.4×10-3 | 3.1×10-3   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.
bAddtional subjects added to the dataset reported by Holstege et al., 2022.

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. 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.
  2. Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, Rousseau S, Richard AC, Rovelet-Lecrux A, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Amouyel P, Munter HM, Bourque G, Lathrop M, Frebourg T, Redon R, Letenneur L, Dartigues JF, Génin E, Lambert JC, Hannequin D, Campion D, CNR-MAJ collaborators. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease. Mol Psychiatry. 2016 Jun;21(6):831-6. Epub 2015 Aug 25 PubMed.
  3. Nicolas G, Acuña-Hidalgo R, Keogh MJ, Quenez O, Steehouwer M, Lelieveld S, Rousseau S, Richard AC, Oud MS, Marguet F, Laquerrière A, Morris CM, Attems J, Smith C, Ansorge O, Al Sarraj S, Frebourg T, Campion D, Hannequin D, Wallon D, Gilissen C, Chinnery PF, Veltman JA, Hoischen A. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease. Alzheimers Dement. 2018 Dec;14(12):1632-1639. Epub 2018 Aug 13 PubMed.
  4. 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.
  5. 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.
  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. 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.
  8. 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.
  9. Holstege H, deWaal MW, Tesi N, vanderLee SJ, ADESconsortium, ADSPconsortium, StEP-ADconsortium, Knight-ADRC, UCSF/NYGC/UAB, Vogel M, vanSpaendonk R, Hulsman M, Andersen OM. Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease. 2023 Jul 16 10.1101/2023.07.13.23292622 (version 1) medRxiv.
  10. 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.
  11. 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.
  12. 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.
  13. 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. 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

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