Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121605479 C>A
Position: (GRCh37/hg19):Chr11:121476188 C>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to CAA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 35

Findings

In a study that included 18,959 Alzheimer’s cases and 21,893 control subjects from multiple European and American cohorts, one AD case, age of onset 59 years, carried this variant (Holstege, et al., 2023).

Functional Consequences

Proline-1619 is located in the first of SORL1’s six 3Fn domains—named for fibronectin, the protein in which homologous domains were first described. SORL1’s 3Fn-cassette mediates receptor dimerization, which facilitates retromer-dependent transport of cargo out of endosomes (Jensen et al., 2023). This leucine residue forms part of a structure called the “tyrosine corner,” thought to be critical for maintaining the structural stability of 3Fn domains. Andersen and colleagues predicted that substitutions at proline-1619 are highly likely to increase AD risk (Andersen et al., 2023).

Pathogenic variants were identified at homologous positions in usherin and cardiac myosin-binding protein-C, causing Usher syndrome 2A (USH2A) and familial hypertrophic cardiomyopathy (CMH4), respectively (Andersen et al., 2023).

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References

Paper Citations

1. Holstege H, deWaal MW, Tesi N, vanderLee SJ, ADESconsortium, ADSPconsortium, StEP-ADconsortium, Knight-ADRC, UCSF/NYGC/UAB, Vogel M, vanSpaendonk R, Hulsman M, Andersen OM. Effect of prioritized SORL1 missense variants supports clinical consideration for familial Alzheimer's Disease. 2023 Jul 16 10.1101/2023.07.13.23292622 (version 1) medRxiv.
2. Jensen AM, Kitago Y, Fazeli E, Vægter CB, Small SA, Petsko GA, Andersen OM. Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer. Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2212180120. Epub 2023 Jan 18 PubMed.
3. 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