Mutations

PSEN1 c.*9C>T

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PP1, BP4
Clinical Phenotype: Alzheimer's Disease, Mild Cognitive Impairment
Position: (GRCh38/hg38):Chr14:73219298 C>T
Position: (GRCh37/hg19):Chr14:73686006 C>T
dbSNP ID: rs200464369
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12, 3' UTR

Findings

This variant is in the 3’ untranslated region of PSEN1 mRNA. It was found in a family from the Chinese Familial Alzheimer’s Disease Network (Jia et al., 2020). Carriers of the mutation included three siblings, two sisters diagnosed with Alzheimer’s disease (AD) and a brother diagnosed with mild cognitive impairment (MCI). The two AD patients had APOE4/E3 genotypes and ages at onset of 67 and 68 years, while the MCI patient was homozygous for APOE3 and his age at onset was 70. Also, a sister who did not carry the variant remained cognitively healthy at age 76, suggesting segregation with disease. She was also homozygous for APOE3. The deceased mother had suffered from AD with symptoms starting at age 70, but her genotype was unknown.

This variant was also found in four heterozygotes in the gnomAD variant database, two of African ancestry and two of European ancestry (gnomAD, v2.1.1 Mar 2022). The variant was absent from the Chinese millionome database.

Neuropathology
Neuropathology data are unavailable.

Biological Effect
The biological effect of this variant is unknown. However, its PHRED-scaled CADD score was 6.51, well below the threshold of 20 that is commonly used to predict deleteriousness (CADD v1.6, March 2022).

Pathogenicity

Alzheimer's Disease : Uncertain Significance

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

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. c.*9C>T: At least one family with 2 AD carriers and >=1 unaffected noncarriers.

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: 09 Mar 2022

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

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.

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.

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.