Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121588109 T>C
Position: (GRCh37/hg19):Chr11:121458818 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TGC to CGC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 28

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 AD cases (Henne Holstege, personal communication).

Functional Consequences

Cysteine-1302 is located in the sixth of SORL1's 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Each CR contains six conserved cysteines. Variants resulting in an odd number of cysteines—either through substitution of one of these six cysteines, as in C1302R, or mutation of another residue to cysteine—may disrupt disulfide bridging. Based on domain mapping of disease mutations, Andersen and colleagues predicted that variants containing an odd number of cysteines in a CR domain (ONC variants) are highly likely to increase AD risk (Andersen et al., 2023): Approximately 40 percent of variants in LDLR linked to familial hypercholesterolemia are ONC variants, and ONC variants in LRP4 and LRP5 have been linked to Cenani–Lenz syndactyly syndrome and exudative vitreoretinopathy 4, respectively. Indeed, analysis of data from the Alzheimer’s Disease Sequencing Project and the Alzheimer Disease European Sequencing consortium showed that SORL1 ONC variants significantly increased the risk of AD (OR = 6.31 95% CI: 2.45 -16.24, p=5.1x10^-6; Fisher Exact test) (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