Mutations

PSEN1 V94M

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637697 G>A
dbSNP ID: rs63750831
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTG to ATG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was first identified in a single patient from Colombia diagnosed with probable Alzheimer’s disease according to NINCDS-ADRDA criteria. The patient, known as patient 189, experienced symptom onset at age 53, but had no family history of dementia. Mutation segregation with the disease could not be determined, as DNA from family members was unavailable. The reporting authors suspected pathogenicity based on the conservation of the amino acid in other species and the absence of the mutation in 53 control subjects (Arango et al., 2001).

Of note, a compilation of information on dominantly inherited AD in Latin America reported the variant has been found in two Colombian families including 23 individuals (Llibre-Guerra et al., 2021).

The variant had an allele count of 2 and frequency 0.0008 percent in the gnomAD variant database (Koriath et al., 2018).

Neuropathology

Unknown.

Biological Effect

An in vitro assay using purified proteins to test the ability of the variant to cleave the APP-C99 substrate revealed decreased Aβ42 and Aβ40 production, but the Aβ42/Aβ40 ratio was similar to that generated by wild-type PSEN1 (Sun et al. 2017).

Although 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), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).. 

Koriath and co-workers predicted the variant has reduced penetrance (Koriath et al., 2018).

Last Updated: 16 Sep 2021

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References

Paper Citations

  1. . Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet. 2001 Oct 1;103(2):138-43. PubMed.
  2. . Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes. Alzheimers Dement. 2021 Apr;17(4):653-664. Epub 2020 Nov 23 PubMed.
  3. . 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.
  4. . 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. . 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. CADD v.1.6

Further Reading

Papers

  1. . Presenilin mutations in a Colombian familial and sporadic AD sample. Neurobiol Aging. 2000 May-Jun;;21(Supp 1):176

Protein Diagram

Primary Papers

  1. . Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet. 2001 Oct 1;103(2):138-43. PubMed.

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