Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121470023 C>T
Position: (GRCh37/hg19):Chr11:121340732 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TCC to TTC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 2

Findings

This variant was found in a Swedish Alzheimer’s patient (age of onset 60 years) in a cohort of 1255 early onset AD cases and 1938 controls from the European Early Onset Dementia Consortium (Verheijen et al., 2016). There was no known family history of AD. This carrier was also mentioned in three subsequent studies (Campion et al., 2019; Holstege et al., 2017; Thonberg et al., 2017).

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

Functional Consequences

The serine to phenylalanine substitution was predicted to be probably damaging by PolyPhen-2, damaging by SIFT, and disease causing by Mutation Taster; the calculated Gibbs free energy change indicated reduced protein stability (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.
4. 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.

Further Reading

No Available Further Reading