Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659552 T>C
dbSNP ID: rs63751163
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTG to TCG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in a screening of the British St. Mary’s and National hospitals’ collection of familial AD pedigrees (Hutton et al., 1996). Clinical information from five family members revealed a median age of onset of 52 years, with duration varying between six and 15 years. Three patients presented with pronounced myoclonus (without seizures), depression, and psychosis (Harvey et al., 1998). Co-segregation of the variant with disease was reported based on genotyping one affected and one unaffected family member. The variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
In two cases, neuropathology was consistent with AD (Harvey et al., 1998).

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed PSEN1 L250S generates less Aβ40 and Aβ42 peptides than the wild-type protein, and increases the Aβ42/Aβ40 ratio 10-fold (Sun et al., 2017).

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).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Hutton M, Busfield F, Wragg M, Crook R, Perez-Tur J, Clark RF, Prihar G, Talbot C, Phillips H, Wright K, Baker M, Lendon C, Duff K, Martinez A, Houlden H, Nichols A, Karran E, Roberts G, Roques P, Rossor M, Venter JC, Adams MD, Cline RT, Phillips CA, Goate A. Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. Neuroreport. 1996 Feb 29;7(3):801-5. PubMed.
2. Harvey RJ, Ellison D, Hardy J, Hutton M, Roques PK, Collinge J, Fox NC, Rossor MN. Chromosome 14 familial Alzheimer's disease: the clinical and neuropathological characteristics of a family with a leucine-->serine (L250S) substitution at codon 250 of the presenilin 1 gene. J Neurol Neurosurg Psychiatry. 1998 Jan;64(1):44-9. PubMed.
3. 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.
4. 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

Further Reading