Mutations

PSEN2 A237V

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227076673 C>T
dbSNP ID: rs200670135
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCG to GTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8

Findings

This variant was found in an exome sequencing study of 141 individuals with late-onset Alzheimer’s disease and 179 elderly controls without neuropathology at the time of their deaths. The mutation carrier was a Caucasian man who was diagnosed with AD at the age of 87. His APOE genotype was ε3/ε3. He had no known family history of dementia (Sassi et al., 2014).

In silico, the variant was predicted to be possibly damaging, and classified as probably pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Sassi et al., 2014). However, in a subsequent study, the variant was described as "most likely benign" or causing an "only small increase in risk" based on its allele count and frequency in the gnomAD variant database: 14 and 0.0056 percent, respectively (Koriath et al., 2018 /papers/predictors-dementia-gene-mutation-based-gene-panel-next-generation-sequencing-large-dementia). The penetrance was calculated to be two percent or less.

Neuropathology

The individual described by Sassi and colleagues had neuropathology consistent with AD (Sassi et al., 2014).

Biological Effect

Unknown. In silico, this variant is predicted to be possibly damaging (Sassi et al., 2014).

Last Updated: 16 Jul 2019

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References

Paper Citations

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-6. Epub 2014 Jun 16 PubMed.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

Papers

  1. . The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine. Genome Res. 2009 Sep;19(9):1665-74. Epub 2009 Jul 14 PubMed.

Protein Diagram

Primary Papers

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-6. Epub 2014 Jun 16 PubMed.

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