Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121514191 G>C
Position: (GRCh37/hg19):Chr11:121384900 G>C
dbSNP ID: rs776374954
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to CTG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 8

Findings

The V361L variant was identified in a patient clinically diagnosed with frontotemporal dementia and lacking cerebrospinal fluid or PET imaging biomarkers of Alzheimer’s disease (Sun et al., 2021). This patient developed symptoms at 28 years of age, and it is not known whether she has a family history of FTD.

This variant is classified as of uncertain significance by the criteria of the American College of Medical Genetics and Genomics.

Functional Consequences

Valine-361 is part of a stretch of hydrophobic residues that is conserved among the blades of the VPS10P β-propeller. These hydrophobic motifs are thought to have a role in stabilizing the β-propeller. Andersen and colleagues have predicted that non-conservative substitutions at this position will have a moderate effect on disease-risk (Andersen et al., 2023). However, substitution of valine with leucine, another hydrophobic residue, might be tolerated.

The V361L variant was predicted to be deleterious by PolyPhen-2 and Mutation Taster, but likely benign by M-CAP (Mendelian Clinically Applicable Pathogenicity).

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References

Paper Citations

1. Sun L, Zhang J, Su N, Zhang S, Yan F, Lin X, Yu J, Li W, Li X, Xiao S. Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing. Front Aging Neurosci. 2021;13:745407. Epub 2021 Oct 14 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