Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121555302 G>C
Position: (GRCh37/hg19):Chr11:121426011 G>C
dbSNP ID: rs201992414
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to GCC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 18

Findings

The G852A variant was identified in a screen of 124 Alzheimer’s patients with a family history of AD (at least one affected first-degree relative) recruited from a memory clinic in Madrid (Gómez-Tortosa et al., 2018). The carrier began exhibiting symptoms at 66 years of age and died at age 72. In addition to the cognitive decline typical of AD, she experienced seizures and myoclonus late in her disease course. Her APOE genotype was E3/E4. DNA was not available from relatives, precluding segregation analysis.

The variant was absent from a control group of 200 Spanish individuals 69 to 95 years of age.

Subsequently, the G852A variant was found in a single control subject in a sample of 18,959 AD cases and 21,893 controls from multiple European and American cohorts (Henne Holstege, personal communication).

This variant is classified as “uncertain: possibly pathogenic” by the criteria of Holstege et al. (Holstege et al., 2017) and of uncertain pathogenicity by the guidelines of the American College of Genetics and Genomics.

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References

Paper Citations

1. 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.
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.

Further Reading

No Available Further Reading