Overview

Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr11:121367738 A>G
dbSNP ID: rs758629470
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to GTG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 6

Findings

In a study of 1255 cases and 1938 controls from the European Early Onset Dementia Consortium, an Italian woman with early-onset AD (age of onset 59 years) was found to be a heterozygous carrier of this variant (Verheijen et al., 2016).

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

The M307V variant is classified as uncertain, but possibly pathogenic by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

Methionine-307 is part of a stretch of hydrophobic residues that is conserved among the blades of the VPS10P β-propeller. These hydrophobic motifs are thought to have a role in stabilizing the β-propeller. Andersen and colleagues have predicted that non-conservative substitutions at this position will have a moderate effect on disease-risk (Andersen et al., 2023). However, substitution of methionine with valine, another hydrophobic residue, might be tolerated.

The methionine-to-valine substitution was predicted to be damaging by SIFT, disease-causing by Mutation Taster, and benign 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. 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.
3. 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