Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PM1, PP2, PP3, BS1, BS2, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73170989 G>A
Position: (GRCh37/hg19):Chr14:73637697 G>A
dbSNP ID: rs63750831
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

Although a compilation of information on dominantly inherited Alzheimer’s disease in Latin America reported this variant in two Colombian families with AD (Llibre-Guerra et al., 2020), it has also been found in a healthy control (Wang et al., 2023) and in eight carriers in the gnomAD variant database (v4.0.0, Jan 2024). Moreover, cell-based and in vitro assays have failed to detect a biological effect associated with this substitution.

V94M was first identified in a 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).

More recently, the variant was identified in a cognitively healthy control in a study of late-onset AD. As reported in a preprint, the study analyzed data from the U.S.-based Alzheimer’s Disease Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 13,825 cases and 14,715 controls (Wang et al., 2023, suppl table e-5).

The variant had an allele count of 8 and a global frequency 0.000005 in the gnomAD variant database (v4.0.0, Jan 2024). The highest frequency (0.000067) was reported in individuals of admixed American ancestry, with an allele count of 3.

Neuropathology

Neuropathological data are unavailable.

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, and the Aβ42/Aβ40 ratio was similar to that generated by wild-type PSEN1 (Sun et al. 2017). These findings were consistent with analyses of the conditioned media of human embryonic kidney cells lacking endogenous PSEN1 and PSEN2 and expressing this variant. In this case, both the Aβ42/Aβ40 and the Aβ37/Aβ42 ratios were similar to those measured in the media of control cells expressing wild-type PSEN1 (Liu et al., 2022; Apr 2022 news). Of note, both ratios proved useful for distinguishing control versus AD samples, with Aβ37/Aβ42 outperforming Aβ42/Aβ40.

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).

Pathogenicity

Alzheimer's Disease : Benign*

*This variant may have reduced penetrance, a condition outside the scope of the ACMG-AMP guidelines.

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

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References

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022

Paper Citations

1. Llibre-Guerra JJ, Li Y, Allegri RF, Mendez PC, Surace EI, Llibre-Rodriguez JJ, Sosa AL, Aláez-Verson C, Longoria EM, Tellez A, Carrillo-Sánchez K, Flores-Lagunes LL, Sánchez V, Takada LT, Nitrini R, Ferreira-Frota NA, Benevides-Lima J, Lopera F, Ramírez L, Jiménez-Velázquez I, Schenk C, Acosta D, Behrens MI, Doering M, Ziegemeier E, Morris JC, McDade E, Bateman RJ. 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.
2. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, The Alzheimer's Disease Sequencing Project, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.
3. Arango D, Cruts M, Torres O, Backhovens H, Serrano ML, Villareal E, Montañes P, Matallana D, Cano C, Van Broeckhoven C, Jacquier M. 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.
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. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; 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. CADD v.1.6

Further Reading