Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121621172 G>A
Position: (GRCh37/hg19):Chr11:121491881 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GGG to AGG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 44

Findings

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

In a Dutch sample of 640 Alzheimer’s cases and 1268 controls, a 60-year-old AD case was found to be a heterozygous carrier of this variant. No additional carriers were found in a pan-European cohort of 1255 AD cases and 1938 controls (Holstege et al., 2017). The cohorts comprising the Dutch sample contributed to the 2022 study cited above.

One carrier of this variant has been described in detail, a Spanish woman diagnosed with probable Alzheimer’s disease (Alvarez-Mora et al., 2022). This patient experienced progressive memory decline, first noticed at age 67, and was diagnosed with amnestic mild cognitive impairment at age 69. She had previously sought medical advice for apathy and depression, at age 63. Cognitive signs worsened over time, and she died with advanced dementia at age 75. MRI three years after symptom onset showed mild global brain atrophy, and SPECT imaging showed hypoperfusion of the temporal and posterior parietal lobes. There was a family history of AD: The patient’s father had been diagnosed with early onset AD—with symptom onset at age 55—and five of his siblings were reported to have had late-onset AD, all older than 80 years of age at symptom onset.

The G2000R variant is classified as likely pathogenic by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

The G2000R 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, 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. Alvarez-Mora MI, Blanco-Palmero VA, Quesada-Espinosa JF, Arteche-Lopez AR, Llamas-Velasco S, Palma Milla C, Lezana Rosales JM, Gomez-Manjon I, Hernandez-Lain A, Jimenez Almonacid J, Gil-Fournier B, Ramiro-León S, González-Sánchez M, Herrero-San Martín AO, Pérez-Martínez DA, Gómez-Tortosa E, Carro E, Bartolomé F, Gomez-Rodriguez MJ, Sanchez-Calvin MT, Villarejo-Galende A, Moreno-Garcia M. Heterozygous and Homozygous Variants in SORL1 Gene in Alzheimer's Disease Patients: Clinical, Neuroimaging and Neuropathological Findings. Int J Mol Sci. 2022 Apr 11;23(8) 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.

Further Reading

No Available Further Reading