Mutations

PSEN1 R35Q

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP2, BS1, BS3, BP4
Clinical Phenotype: Alzheimer's Disease, None
Reference Assembly: GRCh37/hg19
Position: Chr14:73637521 G>A
dbSNP ID: rs63750592
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CGG to CAG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

Although this coding variant has been identified in at least four individuals with Alzheimer's disease (AD), several lines of evidence indicate it may be a benign polymorphism. It was first detected in one of 414 AD patients who were thought to carry genetic risk factors. Segregation analysis was not possible (Rogaeva et al., 2001). Subsequently, whole-exome sequencing identified this variant in one of 424 French people with early onset AD, but clinical details were not reported (Nicolas et al., 2015). The variant was also reported in a Han Chinese woman with AD and a family history of dementia (Mao et al., 2021). Her age at onset was 63 years. She had an APOE3/E3 genotype.

The variant was also found in a control African Mozabite individual among 130 DNA samples obtained from the Centre d'Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP) (Guerreiro et al., 2010). The age of this individual was not reported, so it is uncertain whether they were past the expected age at onset. Another carrier was identified in a cohort of Italian patients diagnosed with early onset AD (Bartoletti-Stella et al., 2022). Of note, this individual, who had no family history of AD, also carried the PSEN2 G223A variant, which was considered pathogenic or likely pathogenic and classified as "diagnostic" according to guidelines developed by Cochran et al., 2019.

The variant is found at a frequency of 0.0002 with an allele count of 56 in the gnomAD variant database (gnomAD v2.1.1, Sep 2021).

Neuropathology

Neuropathological data are unavailable for this variant.

Biological Effect

Several assays indicate this variant has no effect, or a very minor effect, on APP processing. The most comprehensive assessment, a study of mouse embryonic fibroblasts expressing the variant on a PSEN null background and transduced with human APP-C99, showed R35Q's Aβ profile was virtually identical to that of cells expressing wildtype PSEN1 (Petit et al., 2022, Apr 2022 news). In particular, the Aβ (37 + 38 + 40) / (42 + 43) ratio, an indicator of AD pathogenicity that correlated with AD age at onset, was very similar to controls. Consistent with these findings, a cellular assay using mouse neuroblastoma cells expressing the mutant protein showed secretion of similar amounts of Aβ42 and Aβ40 as cells expressing wild-type PSEN1, with no effect on the Aβ42/Aβ40 ratio (Hsu et al., 2020).

An assay using purified proteins to test R35Q's ability to cleave the APP-C99 substrate indicated some alterations in the mutant's APP processing capabilities, but their pathogenicity remains uncertain (Sun et al., 2017). The assay, which appears to be limited in its cleavage efficiency (Liu et al., 2021), revealed only a modest elevation of the Aβ42/Aβ40 ratio and decreased levels of Aβ40 and Aβ42.  

R35 is not conserved between PSEN1 and PSEN2 and in silico algorithms to predict the effects of R35Q 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). Moreover, this variant's PHRED-scaled CADD score failed to reach 20, a threshold used to predict deleteriousness (CADD, v.1.6, Jan 2022).

The variant has been classified as "not pathogenic" (Hsu et al., 2020), a "variant of uncertain significance" (Mao et al., 2021), and a risk factor (Bartolleti-Stella et al., 2022).

Pathogenicity

Alzheimer's Disease : Benign

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

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  R35Q: Most carriers were of European ancestry.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

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: 17 Nov 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. . 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. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  3. . Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
  4. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
  5. . Dementia-related genetic variants in an Italian population of early-onset Alzheimer's disease. Front Aging Neurosci. 2022;14:969817. Epub 2022 Sep 5 PubMed.
  6. . Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles. Cold Spring Harb Mol Case Stud. 2019 Dec;5(6) Print 2019 Dec PubMed.
  7. . Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
  8. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  9. . 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.
  10. . Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021 Jan-Jun;296:100393. Epub 2021 Feb 8 PubMed.
  11. . 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

Further Reading

Papers

  1. . Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Alzpedia

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