Mutations

SORL1 I425V

Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121520718 A>G
Position: (GRCh37/hg19):Chr11:121391427 A>G
dbSNP ID: rs773908330
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: ATT to GTT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 9

Findings

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, this allele was observed once among the controls (Holstege et al., 2022).

Functional Consequences

Isoleucine -425 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 isoleucine with valine, another hydrophobic residue, might be tolerated. Indeed, among 40 species examined, isoleucine was found at the homologous position in 36 cases, but valine occurred in this position in four cases.

Last Updated: 18 Jul 2024

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References

Paper Citations

  1. . Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
  2. . 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

Protein Diagram

Primary Papers

  1. . Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
  2. . 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.

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