Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121520691 C>T
Position: (GRCh37/hg19):Chr11:121391400 C>T
dbSNP ID: rs144585461
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Nonsense
Codon Change: CGA to TGA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 9

Findings

This protein-truncating variant was found in a Swedish woman of Chilean origin, in a study of 1255 early onset AD cases and 1938 controls from the European Early Onset Dementia Consortium. This heterozygous carrier had an age of onset of 55 years, but it is not known whether there was a family history of dementia (Verheijen et al., 2016, 27026413; Thonberg et al., 2017, 28595629).

The variant was not found in a Dutch cohort of 640 cases and 1268 controls (Holstege et al., 2017).

This variant is classified as pathogenic by the criteria of Holstege et al. (Holstege et al., 2017) and as likely pathogenic by the criteria of the American College of Medical Genetics and Genomics (Thonberg et al., 2017).

Functional Consequences

The R416Ter variant is predicted to be disease-causing by Mutation Taster (Verheijen et al., 2016).

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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. Thonberg H, Chiang HH, Lilius L, Forsell C, Lindström AK, Johansson C, Björkström J, Thordardottir S, Sleegers K, Van Broeckhoven C, Rönnbäck A, Graff C. Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene. Acta Neuropathol Commun. 2017 Jun 9;5(1):43. 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.

Further Reading

No Available Further Reading