Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121545302 G>A
Position: (GRCh37/hg19):Chr11:121416011 G>A
dbSNP ID: rs1196349652
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to AAG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 14

Findings

In a cohort of 1255 European Alzheimer’s cases and 1938 controls from the European Early Onset Dementia Consortium, an Italian control subject (age 55 years) was found to be a heterozygous carrier of this variant (Verheijen et al., 2016).

No additional carriers were found among 5198 AD cases and 4491 controls from the Alzheimer’s Disease Sequencing Project from whom whole-exome sequencing data were available, 1779 AD cases and 1273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) project, 332 cases and 676 controls of European ancestry from the United Kingdom and North America (Campion et al., 2019), or 640 cases and 1268 controls from a multi-center Dutch sample (Holstege et al., 2017).

The E642K variant is classified as “uncertain: possibly pathogenic” by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

The glutamate-to-lysine substitution at amino acid 642 was predicted to be tolerated by SIFT, disease-causing by Mutation Taster, and probably damaging by PolyPhen-2 (Verheijen et al., 2016).

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References

Paper Citations

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.
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, 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