Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121583538 G>T
Position: (GRCh37/hg19):Chr11:121454247 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAT to TAT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 26

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 three times—twice among the AD cases and once 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. Aspartate-1221, within CR4, is a so-called “fingerprint” residue. As substitutions at fingerprint residues impair ligand binding in other proteins containing CR domains, Andersen and colleagues predicted that SORL1 mutations affecting fingerprint residues are moderately likely to increase AD risk (Andersen et al., 2023).

A pathogenic variant was identified in a homologous position in LDLR (linked to familial hypercholesterolemia 1) (Andersen et al., 2023).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

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