Mutations

PSEN2 c.887-3C>T

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, BP4, BP5
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226891275 C>T
Position: (GRCh37/hg19):Chr1:227078976 C>T
dbSNP ID: rs1230394996
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Intron 9

Findings

This splice-site mutation was found in a Han Chinese individual diagnosed with probable AD according to the NINCDS-ADRDA and DSM-IV criteria (Wang et al., 2019).  The patient had a family history of AD and was APOE4 positive. Age at onset was 81 years. The mutation was absent from 160 controls and from the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology
Unknown

Biological Effect
The biological effect of this mutation is unknown, but in silico analysis indicated a low likelihood of being deleterious (PHRED-scaled CADD score of 9.977). The pathogenicity of the mutation was described as unclear given the late age at onset and the presence of an APOE4 allele (Wang et al., 2019).

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: only one affected carrier has been reported without co-segregation data, and the variant 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.

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.

BP5-P

Variant found in a case with an alternate molecular basis for disease.

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. Wang G, Zhang DF, Jiang HY, Fan Y, Ma L, Shen Z, Bi R, Xu M, Tan L, Shan B, Yao YG, Feng T. Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease. J Psychiatr Res. 2019 Jun;113:141-147. Epub 2019 Mar 30 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Wang G, Zhang DF, Jiang HY, Fan Y, Ma L, Shen Z, Bi R, Xu M, Tan L, Shan B, Yao YG, Feng T. Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease. J Psychiatr Res. 2019 Jun;113:141-147. Epub 2019 Mar 30 PubMed.

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