Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121588108 G>T
Position: (GRCh37/hg19):Chr11:121458817 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CAG to CAT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 28

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, and ligand binding is Ca²⁺-dependent. In proteins with CR domains, each CR contains an octahedral Ca²⁺ cage critical for proper folding of the domain. Residue 1301 is a component of the Ca²⁺ cage in CR6, and substitution of glutamine with histidine is expected to disrupt Ca²⁺ binding.

Andersen and colleagues predicted that variants affecting residues that form the Ca²⁺ cages are highly likely to increase AD risk (Andersen et al., 2023). Domain mapping of disease mutations revealed that several variants associated with medical conditions—in genes including LDLR (familial hypercholesterolemia), LRP2 (intellectual disability, Stickler syndrome), LRP5 (exudative vitreoretinopathy 4), TMPRSS3 (deafness), and TMPRSS6 (iron-refractory iron deficiency anemia)—occur in Ca²⁺-cage residues. Furthermore, analysis of data from the Alzheimer’s Disease Sequencing Project and the Alzheimer Disease European Sequencing consortium showed that SORL1 Ca²⁺-cage variants significantly increased the risk of AD (OR = infinity), leading to the suggestion that these variants be considered causative for AD (Andersen et al., 2023).

The following Ca²⁺-cage variants are listed in the Alzforum database: D1108N, D1182N, D1219G, D1261G, D1267N, D1267E, Q1301H, D1345N, D1439N, D1502G, D1535N, D1545N, D1545G, D1545E. With the exception of D1267E, all carriers of these variants were Alzheimer’s cases.

The variant was predicted to be benign by PolyPhen-2 (Vardarajan et al., 2015).

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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