Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121570231 G>A
Position: (GRCh37/hg19):Chr11:121440940 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to AAC
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 23

Findings

A Saudi Arabian Alzheimer’s patient, 62 years old at symptom onset, was found to be a heterozygous carrier of this variant (El Bitar et al., 2019). The carrier’s brother was also diagnosed with AD, but with a later age of onset—73 years. DNA was not available from the proband’s relatives, precluding segregation analysis.

The variant was not seen in the ExAC, 1000 Genomes, or Saudi Human Genome Program databases at the time of its publication (El Bitar et al., 2019).

The D1100N variant was classified as “uncertain: possibly pathogenic” by the criteria of Holstege et al. (Holstege et al., 2017).

Functional Consequences

The SORL1 protein contains 11 complement-type repeats (CRs). A majority of known SORL1 ligands, including APP, bind to the CR cluster. Aspartate-1100, within CR1, is a so-called “fingerprint” residue. As substitutions at fingerprint residues impair ligand binding in other proteins containing CR domains, Andersen and colleagues predicted that SORL1 mutations affecting fingerprint residues are moderately likely to increase AD risk (Andersen et al., 2023).

A pathogenic variant was identified in a homologous position in LDLR (linked to familial hypercholesterolemia 1) (Andersen et al., 2023).

The variant was predicted to be tolerated by SIFT and benign by PolyPhen-2, but disease-causing by Mutation Taster and deleterious by PROVEAN (El Bitar et al., 2019).

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References

Paper Citations

1. El Bitar F, Qadi N, Al Rajeh S, Majrashi A, Abdulaziz S, Majrashi N, Al Inizi M, Taher A, Al Tassan N. Genetic Study of Alzheimer's Disease in Saudi Population. J Alzheimers Dis. 2019;67(1):231-242. PubMed.
2. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 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