Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885623 G>A
Position: (GRCh37/hg19):Chr1:227073324 G>A
dbSNP ID: rs63750812
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to ATC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This variant was the third in PSEN2 to be reported. It was identified in a single Spanish individual diagnosed with late-onset Alzheimer's disease. The patient developed symptoms at age 76. There was a positive family history for dementia, but details were not available and segregation could not be assessed (Lao et al., 1998). The variant was described as most likely having reduced penetrance, with an allele count of two, and a frequency of 0.0008 percent in the gnomAD variant database (Koriath et al., 2018). A more recent search of the gnomAD variant database revealed five heterozygotes, most of European ancestry (v2.1.1, Nov 2021).

Neuropathology

Unknown.

Biological Effect 

When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the V148I variant did not affect steady-state levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared to wild-type PSEN2. When co-transfected with APP carrying the Swedish mutation, V148I PSEN2 did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005). However, a subsequent study using human embryonic kidney cells revealed an elevation of the Aβ42/Aβ40 ratio (V148I: 0.18 vs WT:0.15) and a decrease in the Aβ37/Aβ42 ratio (V148I: 0.32 vs WT:0.44) (Liu et al., 2024 preprint). The latter has been reported to outperform the former as an indicator of AD pathogenicity for PSEN1 variants (Liu et al., 2022, Apr 2022 news).

Comparing V148I to its PSEN1 homolog V142I provides information that supports both pathogenic and non-pathogenic effects. On the one hand, PSEN1 V142I has been classified as likely pathogenic and, as described in a preprint, PSEN2 variants with pathogenic PSEN1 homologs appear to be more likely classified as pathogenic than those without (Liu et al., 2024). On the other hand, across multiple PSEN1 and PSEN2 variants, the effects of PSEN1/PSEN2 homologs were correlated. In this case, PSEN1 V142I had little or no effect on both the Aβ42/Aβ40 (V142I: 0.15 vs WT:0.15) and Aβ37/Aβ42 (V142I: 0.40 vs WT:0.41) ratios. 

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

Pathogenicity

Alzheimer's Disease : Uncertain Significance

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

Mutations Citations

1. PSEN1 V142I

Paper Citations

1. Lao JI, Beyer K, Fernández-Novoa L, Cacabelos R. A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer's disease. Neurogenetics. 1998 Aug;1(4):293-6. PubMed.
2. 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.
3. Walker ES, Martinez M, Brunkan AL, Goate A. Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.
4. 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.
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.

Further Reading

No Available Further Reading