Mutations

PSEN1 c.*947G>A

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: BS2, BP4
Position: (GRCh38/hg38):Chr14:73220236 G>A
Position: (GRCh37/hg19):Chr14:73686944 G>A
dbSNP ID: rs7523
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 common variant was reported as being associated with increased thickness of cortical regions typically affected by Alzheimer’s disease (Seo et al., 2020). The study examined 274 cognitively normal adults 55 years or older, 137 individuals with mild cognitive impairment, and 94 patients with AD dementia from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). MRI imaging revealed reduced thickness in the inferior frontal and orbitofrontal cortices, as well as in the basal ganglia of non-carriers compared with those of carriers (P = 2.5 × 10−5, k = 1497). The odds ratio of the association was 0.39 (95 percent CI, 0.25–0.60; P = 1.7 × 10−5).

The frequency of this variant in the KBASE cohort is 0.161, similar to that found worldwide (0.1424, gnomAD v2.1.1, Jan 2022). Of note, it is also found at a similar frequency in HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death (HEX, Jan 2022).

Pathogenicity

Alzheimer's Disease : Benign*

*This variant was studied in the context of an AD endophenotype, rather than a clinical diagnosis.

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

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

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. Seo J, Byun MS, Yi D, Lee JH, Jeon SY, Shin SA, Kim YK, Kang KM, Sohn CH, Jung G, Park JC, Han SH, Byun J, Mook-Jung I, Lee DY, Choi M, KBASE Research Group. Genetic associations of in vivo pathology influence Alzheimer's disease susceptibility. Alzheimers Res Ther. 2020 Nov 19;12(1):156. PubMed.

Other Citations

  1. HEX

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Seo J, Byun MS, Yi D, Lee JH, Jeon SY, Shin SA, Kim YK, Kang KM, Sohn CH, Jung G, Park JC, Han SH, Byun J, Mook-Jung I, Lee DY, Choi M, KBASE Research Group. Genetic associations of in vivo pathology influence Alzheimer's disease susceptibility. Alzheimers Res Ther. 2020 Nov 19;12(1):156. PubMed.

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