Mutations

PSEN1 S365A

Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PP1, PP2, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73211906 T>G
Position: (GRCh37/hg19):Chr14:73678614 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCC to GCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon10

Findings

This variant was found in  a woman who presented with AD symptoms at age 55, and was not present in her two healthy siblings (Clarimón et al., 2008, Guerreiro et al., 2010). Although the proband’s father suffered from dementia, his age of onset was 70. The variant was present in the gnomAD variant database at a frequency of 0.00001591 with an allele count of 4 and in the gnomAD dataset that excludes data from neurological studies, gnomAD (non-neuro), at a frequency of 0.00001922 with an allele count of 4 (gnomAD v2.1.1, (non-neuro) Aug 2021).

Neuropathology

Unknown.

Biological effect

In one study, in vitro production of Aβ38, Aβ40, Aβ42, and Aβ43, as well as the Aβ42/Aβ40 ratio, were found to be similar to those of wild-type PSEN1 (Matz 2015). A subsequent in vitro study found production of Aβ40 and Aβ42 moderately increased, with no change in the Aβ42/Aβ40 ratio (Sun et al., 2017). However, the phosphorylation status of this site appears to modulate a PSEN1 calcium-triggered conformational change linked to increased Aβ42/Aβ40 (Maesako et al., 2017).

The residue is not conserved between PSEN1 and PSEN2 and is not in a transmembrane domain. Moreover, 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). It was originally classified as possibly pathogenic (Guerreiro et al., 2010). In subsequent studies, it was described as most likely having reduced penetrance (Koriath et al., 2018) and classified as of uncertain significance (Xiao et al., 2021).

 

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-P

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.

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.

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. Clarimón J, Guerreiro R, Lleó A, Guardia C, Blesa F, Gómez-Isla T, Boada M, Bullido MJ, Ferrer I, Martínez-Lage P, Masdeu J, Molina L, Molinuevo JL, Pastor P, Pérez-Tur J, Rey MJ, Sánchez-Valle R, Tàrraga L, Valdivieso F, Singleton A, Hardy J. Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Demen. 2008 Jul;4(4 Suppl):T583.
  2. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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.
  3. Matz A, Halamoda-Kenzaoui B, Hamelin R, Mosser S, Alattia JR, Dimitrov M, Moniatte M, Fraering PC. Identification of new Presenilin-1 phosphosites: implication for γ-secretase activity and Aβ production. J Neurochem. 2015 May;133(3):409-21. Epub 2015 Feb 24 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. Maesako M, Horlacher J, Zoltowska KM, Kastanenka KV, Kara E, Svirsky S, Keller LJ, Li X, Hyman BT, Bacskai BJ, Berezovska O. Pathogenic PS1 phosphorylation at Ser367. Elife. 2017 Jan 30;6 PubMed.
  6. 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.
  7. 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.

External Citations

  1. gnomAD v2.1.1, (non-neuro)

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Clarimón J, Guerreiro R, Lleó A, Guardia C, Blesa F, Gómez-Isla T, Boada M, Bullido MJ, Ferrer I, Martínez-Lage P, Masdeu J, Molina L, Molinuevo JL, Pastor P, Pérez-Tur J, Rey MJ, Sánchez-Valle R, Tàrraga L, Valdivieso F, Singleton A, Hardy J. Genetic screening in a large cohort of early-onset Alzheimer's disease patients from Spain: novel mutations in the amyloid precursor protein and presenilines. Alzheimers Demen. 2008 Jul;4(4 Suppl):T583.
  2. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. 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.

Other mutations at this position

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