Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121619757 G>A
Position: (GRCh37/hg19):Chr11:121490466 G>A
dbSNP ID: rs537754202
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGT to CAT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 43

Findings

In a pan-European cohort of 1255 Alzheimer’s cases and 1938 controls from the European Early Onset Dementia Consortium, a 78-year-old Belgian control subject was found to be a heterozygous carrier of this variant (Verheijen 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, 332 cases and 676 controls of European ancestry from the United Kingdom and North America (Campion et al., 2019), or 640 cases and 1268 controls from a multi-center Dutch sample (Holstege et al., 2017).

The R1910H variant is classified as likely benign by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

Arginine-1910 is located in the fourth of SORL1’s six 3Fn domains—named for fibronectin, the protein in which homologous domains were first described. SORL1’s 3Fn-cassette mediates receptor dimerization, which facilitates retromer-dependent transport of cargo out of endosomes (Jensen et al., 2023). Based on domain mapping of disease mutations, Andersen and colleagues predicted that substitutions at arginine-1910 are highly likely to increase AD risk: They identified nine disease-associated variants at equivalent positions in 3Fn domains in other proteins, eight of which involved replacement of an arginine (Andersen et al., 2023). However, as noted above, the single identified carrier of a SORL1 variant at this position was a control subject.

This variant was predicted to be tolerated by SIFT, disease-causing by Mutation Taster, and probably damaging by PolyPhen-2 (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. Jensen AM, Kitago Y, Fazeli E, Vægter CB, Small SA, Petsko GA, Andersen OM. Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer. Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2212180120. Epub 2023 Jan 18 PubMed.
5. Andersen OM, Monti G, Jensen AM, deWaal M, Hulsman M, Olsen JG, Holstege H. Relying on the relationship with known disease-causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer's disease. 2023 Feb 27 10.1101/2023.02.27.524103 (version 1) bioRxiv.

Further Reading

No Available Further Reading