Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121558761 G>A
Position: (GRCh37/hg19):Chr11:121429470 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to CAG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 20

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 controls (Henne Holstege, personal communication).

Functional Consequences

Arginine-945 is found within the YWTD-repeated β-propeller domain (Andersen et al., 2023). Arginines are found at equivalent positions in five of the six blades of the YWTD-repeated β-propeller, where they are thought to interact with the tyrosines of the YWTD motifs to stabilize the domain. Based on domain mapping of disease mutations, Andersen and colleagues predicted that mutations of arginine-945 are highly likely to increase the risk of Alzheimer’s disease—variants in homologous positions in LRP5 are found in patients with osteoporosis-pseudoglioma syndrome and exudative vitreoretinopathy, in LRP4 in patients with congenital myasthenic syndrome, and a mutation in LRP6 segregated with disease in a family with metabolic syndrome.

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