Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: PP2, BS1, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73211886 G>A
Position: (GRCh37/hg19):Chr14:73678594 G>A
dbSNP ID: rs63751174
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGA to CAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This mutation was found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the United States, Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD. Evidence for co-segregation of this mutation with disease is not available.

The variant's penetrance was calculated to be 2 percent or less based on its allele count and frequency in the gnomAD variant database (11 and 0.0044 percent, respectively) (Koriath et al., 2018). The allele count in the ExAC database, which does not include sequencing data from the Alzheimer's Disease Sequencing Project, was 3 (Hsu et al., 2020). The frequency was 0.00004325 and the allele count was 9 in the gnomAD (non-neuro) dataset which excludes data from neurological studies (gnomAD v2.1.1 (non-neuro), Aug 2021).

Neuropathology
Unknown

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed a drop in Aβ40 and Aβ42 production, and an increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). In contrast, mouse neuroblastoma cells lacking expression of endogenous PSEN1 and PSEN2, and transfected with the R358Q variant, secreted increased amounts of Aβ42 and Aβ40, while the Aβ42/Aβ40 ratio remained unchanged (Hsu et al., 2020). R358Q is conserved between PSEN1 and PSEN2.

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021) and the CADD-PHRED tool, which integrates diverse information, gave it a low deleteriousness score, below 20 (CADD v.1.6, Sep 2021).

Based on its estimated low penetrance, Koriath and colleagues described the variant as "most likely benign" or causing an "only small increase in risk" (Koriath et al., 2018), whereas Hsu and colleagues, emphasizing its effect on Aβ secretion in cells, classified it as "probably pathogenic" (Hsu et al., 2020), and Xiao et al. classified it as "likely pathogenic" (Xiao et al., 2021).

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.

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References

Paper Citations

1. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
2. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
3. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
4. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
5. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. gnomAD v2.1.1 (non-neuro
2. CADD v.1.6
3. Hsu et al., 2020

Further Reading

No Available Further Reading