Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121625209 C>G
Position: (GRCh37/hg19):Chr11:121495918 C>G
dbSNP ID: rs139351633
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GCA to GGA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 46

Findings

In an American cohort of European ancestry, composed of 866 late-onset Alzheimer’s cases with a family history of AD and 324 controls, this variant was found in one AD case; the variant did not show a statistical association with AD in this sample (p = 0.56) (Fernández et al., 2016).

Subsequently, this variant was reported in one of 5198 AD cases and one of 4491 controls in a dataset from the Alzheimer’s Disease Sequencing Project (ADSP), consisting of subjects of non-Hispanic Caucasian ancestry from whom whole-exome sequencing data were available (Campion et al., 2019).

The A2099G variant was selected for genotyping in a North American sample of 217 sporadic early onset AD cases and 169 controls, based on its occurrence in the Exome Variant Server database as a nonsynonymous variant with a minor allele frequency <5 percent. The variant was not found in this cohort (Fernández et al., 2016).

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, including ADSP, this allele was observed once among the AD cases and once among the controls (Holstege et al., 2022).

Functional Consequences

Alanine-2099 is located in the sixth of SORL1’s six 3Fn domains—named for fibronectin, the protein in which homologous domains were first described. SORL1’s 3Fn-cassette mediates receptor dimerization, which facilitates retromer-dependent transport of cargo out of endosomes (Jensen et al., 2023). Andersen and colleagues have described alanine-2099 as contributing to a “hydrophobic glue” that holds together the folds of the 3Fn domain, and they predicted that non-conservative substitutions at this position are moderately likely to increase AD risk (Andersen et al., 2023).

Pathogenic variants were identified at homologous positions in usherin and neural cell adhesion molecule L1 (L1CAM), causing Usher syndrome 2A (USH2A) and hydrocephalus due to stenosis of the aqueduct of Sylvius, respectively (Andersen et al., 2023).

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

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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. 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, 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. Jensen AM, Kitago Y, Fazeli E, Vægter CB, Small SA, Petsko GA, Andersen OM. Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer. Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2212180120. Epub 2023 Jan 18 PubMed.
5. 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.

Further Reading

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