Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121557350 G>A
Position: (GRCh37/hg19):Chr11:121428059 G>A
dbSNP ID: rs150245521
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to ATC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 19

Findings

In a sample of 1255 Alzheimer’s cases and 1938 controls from the European Early Onset Dementia Consortium, a 53-year-old Spanish 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).

Subsequently, 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 once among the controls (Henne Holstege, personal communication).

The V870I variant is classified as likely benign by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

Valine-870 is found within the YWTD-repeated β-propeller domain. This domain appears to form a rigid unit with the VPS10P β-propeller, and the two domains may act in concert to bind large ligands (Andersen et al., 2023). This residue forms part of a hydrophobic core that determines the folding of the six-bladed YWTD-repeated β-propeller. Pathogenic variants were identified in homologous positions in LDLR (linked to familial hypercholesterolemia 1) and LRP5 (found in patients with polycystic liver disease 4 with or without kidney cysts) (Andersen et al., 2023). Andersen and colleagues predicted that substitution of valine-870 with a non-hydrophobic amino acid is moderately likely to increase AD risk, but a conservative substitution like valine-to-isoleucine will be tolerated. Indeed, among 40 species examined, valine was found at the homologous position in 21 cases, while leucine occurred in this position in 19 cases, indicating that valine is not absolutely required.

The variant was predicted to be tolerated by SIFT, neutral by Mutation Taster, and possibly damaging by PolyPhen-2 (Campion et al., 2019).

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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. 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