Mutations

SORL1 K1895K

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121618854 G>A
Position: (GRCh37/hg19):Chr11:121489563 G>A
dbSNP ID: rs17125548
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Silent
Codon Change: AAG to AAA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 42

Findings

This synonymous variant was found in both Alzheimer’s cases and controls in a Dutch sample (Holstege et al., 2017) and a pan-European dataset (Verheijen, et al., 2016), where it did not associate with disease. In addition, three heterozygous carriers were found in a Saudi Arabian sample of 117 Alzheimer’s patients (El Bitar et al., 2019).

An association of the K1895K variant with AD was found in a meta-analysis of data from the International Genetics of Alzheimer’s Project encompassing several thousand cases and controls of European descent (Liu et al., 2017).

The K1895K variant is classified as likely benign by the criteria of Holstege et al. (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

Risk Allele(s) N
Cases | Controls		 aAllele frequency
Cases | Controls		 Reported association measurements Ancestry
(Cohort)		 Reference
Large-scale studies and meta-analyses
A 17008 | 37154   p = 7.15 x 10-5 European
(IGAP)		 Liu et al., 2017
(GWAS)
A 1255 | 1938 0.03 | 0.03 OR = 1.04
[CI: 0.92-1.18]
p = 0.52		 European
(European Early-Onset Dementia Consortium)		 Verheijen et al., 2016
(meta-analysis)
Other studies
A 117 | 0 0.0128 | N.A.   Saudi Arabian
(King Faisal Specialist Hospital & Research Center)		 El Bitar et al., 2019
A 640 | 1268 0.0227 | 0.0241   Dutch
(Rotterdam Study, Amsterdam Dementia Cohort, Alzheimer Centrum Zuidwest Nederland (ACZN), 100-plus Study)		 Holstege et al., 2017

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.

This table is meant to convey the range of results reported in the literature. As specific analyses, including co-variates, differ among studies, this information is not intended to be used for quantitative comparisons, and readers are encouraged to refer to the original papers. Thresholds for statistical significance were defined by the authors of each study. (Significant results are in bold.) Note that data from some cohorts may have contributed to multiple studies, so each row does not necessarily represent an independent dataset. While every effort was made to be accurate, readers should confirm any values that are critical for their applications.

Last Updated: 18 Jul 2024

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References

Paper Citations

  1. 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.
  2. 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.
  3. 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.
  4. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  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.

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