Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121550611 G>A
Position: (GRCh37/hg19):Chr11:121421320 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: TGT to TAT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 16

Findings

SORL1 C736Y was identified in a screen for somatic variants in subjects with Alzheimer’s disease (Nicolas et al., 2018). This variant was found in blood, with an allele fraction of 3.61 percent. The patient’s age of onset was 51 years and his APOE genotype is E3/E3.

Functional Consequences

Adjacent to the VPS10P β-propeller is the 10CC region, named for the 10 cysteine residues that form five disulfide bridges. This region contacts and stabilizes the propeller. Mutations resulting in the loss of one of the ten cysteines likely disrupt the conformation of this region, and Andersen and colleagues have predicted that mutations at this position are highly likely to associate with AD risk (Andersen et al., 2023).

The variant is predicted to be deleterious by SIFT, disease-causing by Mutation Taster, and probably damaging by PolyPhen-2 (Nicolas et al., 2018).

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References

Paper Citations

1. Nicolas G, Acuña-Hidalgo R, Keogh MJ, Quenez O, Steehouwer M, Lelieveld S, Rousseau S, Richard AC, Oud MS, Marguet F, Laquerrière A, Morris CM, Attems J, Smith C, Ansorge O, Al Sarraj S, Frebourg T, Campion D, Hannequin D, Wallon D, Gilissen C, Chinnery PF, Veltman JA, Hoischen A. Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease. Alzheimers Dement. 2018 Dec;14(12):1632-1639. Epub 2018 Aug 13 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