Mutations

PSEN1 T281T

Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: BS1, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198104 G>C
Position: (GRCh37/hg19):Chr14:73664812 G>C
dbSNP ID: rs186495252
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Silent
Codon Change: ACG to ACC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This synonymous variant was found in three siblings diagnosed with AD from the Chinese Familial Alzheimer’s Disease Network (Jia et al., 2020). All carriers had an APOE4/E3 genotype and ages at onset ranged from 62 to 65 years. The deceased mother and brother were also affected, at ages 75 and 65, respectively, but their genotypes were unknown.

This variant was also found in 32 heterozygotes in the gnomAD variant database, most of whom were of East Asian ancestry (gnomAD, v2.1.1 Mar 2022). The variant was absent from the Chinese millionome database.

Neuropathology
Neuropathology data were unavailable.

Biological Effect
The biological effect of this variant is unknown. However, its PHRED-scaled CADD score was 7.35, well below the threshold of 20 that is commonly used to predict deleteriousness (CADD v1.6, March 2022).

Interestingly, a study of the PSEN inhibitor MRK-560 which inhibits the activity of PSEN1, but not PSEN2, identified T281 as one of two amino acids responsible for MRK-560's isoform-dependent sensitivity (Guo et al., 2022).

Pathogenicity

Alzheimer's Disease : Likely Benign

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

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  T281T: Most carriers were of East Asian ancestry.

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: 18 May 2023

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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.
  2. Guo X, Wang Y, Zhou J, Jin C, Wang J, Jia B, Jing D, Yan C, Lei J, Zhou R, Shi Y. Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560. Nat Commun. 2022 Oct 22;13(1):6299. PubMed.

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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