Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121607285 G>A
Position: (GRCh37/hg19):Chr11:121477994 G>A
dbSNP ID: NA
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 37

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

Valine-1721 is located in the second 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). Andersen and colleagues have described valine-1721 as contributing to a “hydrophobic glue” that holds together the folds of the 3Fn domain, and they predicted that non-conservative substitutions at this position are moderately likely to increase AD risk (Andersen et al., 2023). Replacement of valine with the hydrophobic amino acid isoleucine is likely to be tolerated.

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References

Paper Citations

1. 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.
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