Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121590083 T>G
Position: (GRCh37/hg19):Chr11:121460792 T>G
dbSNP ID: rs1380969439
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TTT to TTG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 30

Findings

This variant was identified in one of 211 Alzheimer’s patient of Northern European ancestry (Vardarajan et al., 2015).

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Phenylalanine-1374 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).

The effects of this particular variant are difficult to predict: While the phenylalanine-to-leucine substitution exchanges one hydrophobic amino acid for another, the aromatic ring on phenylalanine is lost. (Interestingly, among 40 species examined, phenylalanine was found at the homologous position in 36 cases, but tyrosine—another hydrophobic amino acid with an aromatic ring—was seen in four.) The variant was predicted to be possibly damaging by PolyPhen and deleterious by SIFT (gnomAD v2.1.1, accessed 2021-10-08).

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References

Paper Citations

1. Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, Reitz C, Reyes-Dumeyer D, Shen Y, Rogaeva E, St George-Hyslop P, Mayeux R. Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015 Feb;77(2):215-27. 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