Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121590097 G>A
Position: (GRCh37/hg19):Chr11:121460806 G>A
dbSNP ID: rs148551848
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to GAC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 30

Findings

In a pan-European cohort of 1255 Alzheimer’s cases and 1938 controls from the European Early Onset Dementia Consortium, a 66-year-old Swedish control was found to be a heterozygous carrier of this variant (Verheijen et al., 2016).

One of 676 controls and none of 332 AD cases was also identified as a carrier in a set of Caucasian subjects from Britain and North America (Sassi 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 project (Campion et al., 2019), or 640 cases and 1268 controls from a multi-center Dutch sample (Holstege et al., 2017).

In a study that included 18,959 Alzheimer’s cases and 21,893 control subjects from multiple European and American cohorts, this allele was observed 15 times—eight times among the AD cases and seven times among the controls (Henne Holstege, personal communication).

The G1379D variant is classified as “uncertain: most likely not pathogenic” by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Glycine-1379 is located in CR8 and is one of a pair of glycines that is conserved in eight of the 11 CRs. Based on this degree of conservation, Andersen and colleagues have predicted that substitutions of glycine at residue 1379 are moderately likely to increase AD risk (Andersen et al., 2023, bioRxiv).

This variant was predicted to be deleterious by SIFT, disease-causing by Mutation Taster, and probably damaging by PolyPhen-2 (Sassi et al., 2016, 27249223; Verheijen et al., 2016, 27026413).

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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. Sassi C, Ridge PG, Nalls MA, Gibbs R, Ding J, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, ARUK Consortium, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Bras J, Goate AM, Singleton AB, Guerreiro R, Hardy J. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease. PLoS One. 2016;11(6):e0150079. Epub 2016 Jun 1 PubMed.
3. 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.
4. 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