Mutations

PSEN2 V148I

Overview

Pathogenicity: Alzheimer's Disease : Benign
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227073324 G>A
dbSNP ID: rs63750812
Coding/Non-Coding: Coding
Mutation Type: Point, 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). Moreover, the gnomAD variant database reported 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). On the other hand, 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).

Last Updated: 04 Nov 2021

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References

Paper Citations

  1. . 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. . 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. . 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . 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.

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