Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121590137 C>T
Position: (GRCh37/hg19):Chr11:121460846 C>T
dbSNP ID: rs2276412
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Silent
Codon Change: AAC to AAT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 30

Findings

This synonymous variant was reported to associate with Alzheimer’s disease in two studies with several thousand cases and controls— a case-control study from the Alzheimer's Disease Genetics Consortium (Reitz et al., 2013) and two meta-analyses of data from the International Genetics of Alzheimer’s Project (Liu et al., 2017; NIAGADS GWAS: Alzheimer's Disease). No association was reported in a smaller European cohort composed of 1255 AD cases and 1938 controls (Verheijen, et al., 2016).

The variant was not associated with MRI markers of brain atrophy or cerebrovascular disease (white matter hyperintensities) in African-American or white participants in the family-based MIRAGE study (Cuenco et al., 2009).

The N1392N variant is classified as likely benign by the criteria of Holstege and colleagues (Holstege et al., 2017).

Functional Consequences

The variant was predicted to be tolerated by SIFT and neutral by PROVEAN, and it was classified as a polymorphism by Mutation Taster (El Bitar et al., 2019).

Table

^aAllele frequencies as reported by study authors or calculated by Alzforum curators from data provided in the study, assuming heterozygosity if not explicitly stated in the paper.

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References

Paper Citations

1. Reitz C, Tosto G, Vardarajan B, Rogaeva E, Ghani M, Rogers RS, Conrad C, Haines JL, Pericak-Vance MA, Fallin MD, Foroud T, Farrer LA, Schellenberg GD, George-Hyslop PS, Mayeux R, . Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP). Transl Psychiatry. 2013;3:e256. PubMed.
2. Liu G, Sun JY, Xu M, Yang XY, Sun BL. SORL1 Variants Show Different Association with Early-Onset and Late-Onset Alzheimer's Disease Risk. J Alzheimers Dis. 2017;58(4):1121-1128. PubMed.
3. 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.
4. T Cuenco K, Lunetta KL, Baldwin CT, McKee AC, Guo J, Cupples LA, Green RC, St George-Hyslop PH, Chui H, DeCarli C, Farrer LA, MIRAGE Study Group. Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease. Arch Neurol. 2008 Dec;65(12):1640-8. PubMed.
5. 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.
6. El Bitar F, Qadi N, Al Rajeh S, Majrashi A, Abdulaziz S, Majrashi N, Al Inizi M, Taher A, Al Tassan N. Genetic Study of Alzheimer's Disease in Saudi Population. J Alzheimers Dis. 2019;67(1):231-242. PubMed.

External Citations

1. NIAGADS GWAS: Alzheimer's Disease
2. NIAGADS GWAS: Alzheimer's Disease

Further Reading

No Available Further Reading