Mutations

PSEN1 N24S

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP2, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73148090 A>G
Position: (GRCh37/hg19):Chr14:73614798 A>G
dbSNP ID: rs200598249
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAT to AGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 3

Findings

This variant was found in a family of the Chinese Familial Alzheimer’s Disease Network in which six family members in the same generation were diagnosed with Alzheimer’s disease (Jia et al., 2020). Five of the affected members were genotyped and found to carry the mutation. Two unaffected carriers did not carry the mutation, but they were only 60 and 56 years old, younger than the family’s mean age at onset of 66 years.  The proband’s APOE genotype was E3/E3.

One allele, from an African-American individual, was reported in the gnomAD variant database (gnomAD v2.1.1, Aug 2021). The allele frequency is 0.000003982.

Neuropathology
Unknown.

Biological Effect
The biological effect of this variant is unknown and in silico algorithms yielded mixed results, with only one of five algorithms (Polyphen2, PANTHER, Mutpred2, PROVEAN, Mutation Taster) predicting a damaging effect (Jia et al., 2020). The PHRED-CADD score was 15.04.

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because data for either a pathogenic or benign classification are lacking: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it is absent, or very rare, in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

BP4-P

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is less than 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022

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References

Paper Citations

  1. Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.

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