Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121577331 A>G
Position: (GRCh37/hg19):Chr11:121448040 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to GTC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 25

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 twice among the controls (Henne Holstege, personal communication).

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Isoleucine-1171 is one of a pair of conserved hydrophobic amino acids—usually isoleucine and phenylalanine—in the N-terminal part of each CR that help to stabilize this region. Andersen and colleagues predicted that substitutions of one of these hydrophobic amino acids are moderately likely to increase AD risk (Andersen et al., 2023).

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References

Paper Citations

1. 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