Mutations
PSEN1 P436S
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Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical
Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685899 C>T
dbSNP ID: rs63749925
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: CCA to TCA
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 12
Findings
This mutation was found in two affected siblings from a family in the UK with members who had been diagnosed with probable or definite AD across two or more generations (Palmer et al., 1999). Disease onset occurred at 50 and 44 years of age. The mutation was absent from 92 controls and from the gnomAD variant database (gnomAD v2.1.1, August 2021).
Neuropathology
Unknown
Biological Effect
In mouse embryonic fibroblasts lacking endogenous PSEN1, the P436S mutant produced less Aβ40, Aβ42, and APP and Notch intracellular domains compared with cells transfected with wild-type PSEN1 (Heilig et al., 2010). Moreover, in an in vitro assay using purified proteins, the mutant produced less Aβ40 than wild-type PSEN1, but similar levels of Aβ42 (Sun et al., 2017). In both cases, P436S increased the Aβ42/Aβ40 ratio. Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).
Pathogenicity
Alzheimer's Disease : Not Classified*
*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because it was found in a single affected family without clear evidence of cosegregation or a robust functional effect, and it is absent, or very rare, in the gnomAD database.
This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.
PS3-M
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. P436S: Functional observations are mixed, but they consistently showed an increase in the Aβ42/Aβ40 ratio.
PM1-M
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2-M
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.
PM5-M
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
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.
PP3-P
Multiple lines of computational evidence support a deleterious effect on the 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 greater than or equal to 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
References
Paper Citations
- Palmer MS, Beck JA, Campbell TA, Humphries CB, Roques PK, Fox NC, Harvey R, Rossor MN, Collinge J. Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. Hum Mutat. 1999;13(3):256. PubMed.
- Heilig EA, Xia W, Shen J, Kelleher RJ. A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem. 2010 Jul 16;285(29):22350-9. PubMed.
- 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.
- 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
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Palmer MS, Beck JA, Campbell TA, Humphries CB, Roques PK, Fox NC, Harvey R, Rossor MN, Collinge J. Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online. Hum Mutat. 1999;13(3):256. PubMed.
Other mutations at this position
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