Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121570171 C>T
Position: (GRCh37/hg19):Chr11:121440880 C>T
dbSNP ID: rs376993434
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 23

Findings

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, three AD cases carried this variant (Holstege et al., 2022). An additional carrier—an AD case—was found when this dataset was expanded to 18,959 AD cases and 21,893 controls. These four carriers were unrelated (Holstege et al., 2023).

Previously, in a Dutch sample of 640 Alzheimer’s cases and 1268 controls, a 51-year-old Alzheimer’s patient was found to be a heterozygous carrier of this variant. No additional carriers were found in a pan-European cohort of 1255 cases and 1938 controls in this study (Holstege et al., 2017). The cohorts comprising the Dutch sample contributed data to the 2022 study cited above.

The variant also was reported in one of 5198 AD cases and none 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 ADSP also contributed data to the 2022 study.

The R1080C 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. Nor was it found by whole- exome or genome sequencing of 866 familial late-onset AD cases and 324 controls in the same study (Fernández et al., 2016).

The R1080C variant is classified as likely pathogenic by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

Arginine-1080 is located in the first of SORL1's 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Each CR contains six conserved cysteines. Variants resulting in an odd number of cysteines—either through substitution of one of these six cysteines or mutation of another residue to cysteine, as in R1080C—may disrupt disulfide bridging. Based on domain mapping of disease mutations, Andersen and colleagues predicted that variants containing an odd number of cysteines in a CR domain (ONC variants) are highly likely to increase AD risk (Andersen et al., 2023): Approximately 40 percent of variants in LDLR linked to familial hypercholesterolemia are ONC variants, and ONC variants in LRP4 and LRP5 have been linked to Cenani–Lenz syndactyly syndrome and exudative vitreoretinopathy 4, respectively. Indeed, analysis of data from the Alzheimer’s Disease Sequencing Project and the Alzheimer Disease European Sequencing consortium showed that SORL1 ONC variants significantly increased the risk of AD (OR = 6.31 95% CI: 2.45 -16.24, p=5.1x10^-6; Fisher Exact test) (Andersen et al., 2023).

The R1080C 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. 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. 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.
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. 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.
5. 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.
6. 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

No Available Further Reading