Mutations

SORL1 H1813Q

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121614890 T>A
Position: (GRCh37/hg19):Chr11:121485599 T>A
dbSNP ID: rs62622819
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CAT to CAA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 41

Findings

The H1813Q variant has been found in both cases and controls in European and American cohorts (Fernández et al., 2016; Holstege et al., 2017; Sassi et al., 2016; Vardarajan et al., 2015; Verheijen et al., 2016).

The variant did not associate with AD in two studies (Fernández et al., 2106; Sassi et al., 2016), in a meta-analysis of five non-overlapping studies including more than 18,000 subjects of European ancestry (Campion et al., 2019), or a mega-analysis of nearly 32,000 subjects from multiple European and American cohorts, which contained datasets included in the aforementioned meta-analysis (Holstege et al., 2022).

The H1813Q variant was seen in both Alzheimer’s patients and unaffected individuals in a family- and cohort-based study of Caribbean-Hispanics (Vardarajan et al., 2015). Joint linkage and association analysis, an analytical method that allows researchers to analyze together data from families and unrelated subjects, indicated that the variant associated with Alzheimer’s disease in this population.

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

Functional Consequences

The H1813Q variant was predicted to be benign by PolyPhen-2 and tolerated by SIFT, but deleterious by Mutation Taster (Campion et al., 2019).

In a study investigating the effects of SORL1 missense mutations on protein processing, the H1813Q 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
A 9204 | 9646 8.21×10-3 | 7.72×10-3 Fixed effect model
OR = 1.10
[CI: 0.87 – 1.39]
p =  0.411
Random effects model
OR = 1.10
[CI: 0.88 – 1.39]
p =  0.397		 European, European American Campion et al., 2019 
(meta-analysis)
early onset AD
3180 | 8970		 7.86×10-3 | 7.58×10-3 Fixed effect model
OR = 1.11
[CI: 0.79 – 1.56]
p = 0.558
Random effects model
OR = 1.11
[CI: 0.79 – 1.57]
p = 0.542		 European, European American
A 15,808 | 16,097 8.54×10-3 | 8.60×10-3 OR = 0.99
[CI: 0.83 – 1.19]
p = 0.94		 Multiple European and American cohorts Holstege et al., 2022
(mega-analysis)
Other studies
A 852 (EOAD) | 927 (LOAD) | 1273 (CTRL) 5.28×10-3 | 4.85×10-3 | 7.07×10-3   French
(Alzheimer Disease Exome Sequencing France (ADESFR))		 Bellenguez et al., 2017; Campion et al., 2019
A 5198 | 4491 8.27×10-3 | 8.13×10-3   Non-Hispanic Caucasian
(Alzheimer’s Disease Sequencing Project (ADSP))		 Campion et al., 2019
T sporadic LOAD
134 | 266		 0 | 1.9×10-3 OR =  0
[CI: N.A.]
p = 0.4776		 European American
(Knight ADRC, NIA-LOAD)		 Fernández et al., 2016
A 640 | 1268 1.17×10-2 | 8.28×10-3   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et. al., 2017
A 332 | 676 0.015 | 9.62×10-3 OR = 1.583
[CI: 0.614 – 3.955]
p = 0.271		 UK and North American Caucasian
(NIH-UCL, Knight ADRC, ADNI, Cache County Study on Memory in Aging)		 Sassi et al., 2016
A 462 (87 families) | 498 8.75×10-3 | 3.01×10-3 bp = 1.50×10-4 Caribbean Hispanic
[family- and cohort-based]		 Vardarajan et al., 2015
A 211 | 0 0.012 | N.A.   North European Vardarajan et al., 2015
A 1255 | 1938 8.76×10-3 | 6.19×10-3   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.
bLinkage and association analysis with PSEUDOMARKER20 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

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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. 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. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.

Other mutations at this position

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