Overview

Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr11:121367648 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to CTC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 6

Findings

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).

Functional Consequences

The SORL1 VPS10P domain resembles a 10-bladed propeller, with the blades arranged around a central tunnel. Valine-277 is part of a stretch of hydrophobic residues conserved among the propeller blades and thought to have a role in the formation of the tunnel, as well as providing a hydrophobic surface that allows small lipophilic ligands to bind within the tunnel (Kitago et al., 2015). 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 valine with leucine, another hydrophobic residue, might be tolerated.

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References

Paper Citations

1. Kitago Y, Nagae M, Nakata Z, Yagi-Utsumi M, Takagi-Niidome S, Mihara E, Nogi T, Kato K, Takagi J. Structural basis for amyloidogenic peptide recognition by sorLA. Nat Struct Mol Biol. 2015 Mar;22(3):199-206. Epub 2015 Feb 2 PubMed.
2. 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