Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173651 G>A
Position: (GRCh37/hg19):Chr14:73640359 G>A
dbSNP ID: rs63751037
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to ATC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was originally reported in a U.K. genetic screen of more than 3,000 samples of patients with dementia (Koriath et al., 2018). The carrier was a man diagnosed with AD who had one known relative with early onset dementia. Age at onset was 54 years. The mutation was absent from genetic variant databases, including ExAC, EVS, 1000G, and gnomAD.

The mutation was also found in a large cohort study in South China in which 14 genes associated with neurodegenerative dementias were sequenced in 1795 patients (Jiao et al., 2021). Two male mutation carriers, both diagnosed with AD, were identified with ages of onset of 54 and 52 years. Both had family histories of disease and homozygous APOE3 genotypes. Although both patients suffered from memory impairment, only one had language impairment and the other had mental and behavioral disturbances. Neither presented with sensory or movement dysfunction.

Neuropathology

Unknown

Biological Effect

As reported in a preprint, this variant had little or no effect on either the Aβ42/Aβ40 (V142I: 0.15 vs WT:0.15) or Aβ37/Aβ42 (V142I: 0.40 vs WT:0.41) ratios in human embryonic kidney cells (Liu et al., 2024). However, V142 is highly conserved across species and its PSEN2 homolog, V148I, altered both Aβ42/Aβ40 and Aβ37/Aβ42.

Although some silico algorithms to predict the effects of this variant on protein function 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).

Based on their proposed pathogenicity algorithm, Koriath and colleagues classified the mutation as deleterious (Koriath et al., 2018) and Jiao and co-workers classified it as pathogenic or likely pathogenic (Jiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

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

Mutations Citations

1. PSEN2 V148I

Paper Citations

1. 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.
2. Jiao B, Liu H, Guo L, Xiao X, Liao X, Zhou Y, Weng L, Zhou L, Wang X, Jiang Y, Yang Q, Zhu Y, Zhou L, Zhang W, Wang J, Yan X, Li J, Tang B, Shen L. The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
3. Liu L, Schultz S, Saba A, Yang H-S, Li A, Selkoe D, Chhatwal J. The pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1. 2024 Jun 28 10.1101/2024.06.22.600217 (version 1) bioRxiv.
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. CADD v.1.6

Further Reading

No Available Further Reading