Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121574347 T>G
Position: (GRCh37/hg19):Chr11:121445056 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: AGT to AGG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 24

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 AD cases (Holstege et al., 2023).

Functional Consequences

Serine-1148 is located in the second of SORL1's 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Along with D1146, S1148 participates in a motif known as an Asx turn, in which the sidechain O of an aspartate or asparagine (hence the name “Asx”) forms a hydrogen bond with the mainchain NH of the amino acid two residues downstream. Andersen and colleagues predicted that substitutions of Asx-turn serines are moderately likely to increase AD risk: While they identified three pathogenic variants at homologous positions in CR domains in LDLR, serine is not fully conserved at equivalent positions in all of SORL1’s CR domains, being found in 10 of SORL1’s 11 CRs (Andersen et al., 2023).

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References

Paper Citations

1. Holstege H, deWaal MW, Tesi N, vanderLee SJ, ADESconsortium, ADSPconsortium, StEP-ADconsortium, Knight-ADRC, UCSF/NYGC/UAB, Vogel M, vanSpaendonk R, Hulsman M, Andersen OM. Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease. 2023 Jul 16 10.1101/2023.07.13.23292622 (version 1) medRxiv.
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