Mutations

PSEN2 P334R

Overview

Pathogenicity: Alzheimer's Disease : Benign
Clinical Phenotype: Alzheimer's Disease, None
Reference Assembly: GRCh37/hg19
Position: Chr1:227079474 C>G
dbSNP ID: rs63750207
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCT to CGT
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 11

Findings

This variant was detected in a large Spanish kindred with familial late-onset Alzheimer's disease. The proband began experiencing memory impairment at age 80 and was diagnosed with AD. The proband had three affected siblings and a cousin, but the variant did not segregate with the disease. In addition, the variant was found in one of 165 unrelated individuals and is thought to be a rare polymorphism (Lleó et al., 2002).

Twelve heterozygotes were reported in the gnomAD variant database, 10 with non-Finnish European ancestry (gnomAD v2.1.1 Nov 2021).

Neuropathology

Not applicable.

Biological Effect

Unknown. The P334R residue is not conserved in PSEN1, and two in silico algorithms (SIFT and PolyPhen) predicted it is not deleterious (Hsu et al., 2020). Moreover, its PHRED-scaled CADD score, which integrates diverse information in silico, was below 20, a threshold commonly used to predict  deleteriousness (CADD v.1.6, Nov 2021). Hsu and colleagues classified this variant as "not pathogenic."

Last Updated: 10 Nov 2021

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References

Paper Citations

  1. . Uncommon polymorphism in the presenilin genes in human familial Alzheimer's disease: not to be mistaken with a pathogenic mutation. Neurosci Lett. 2002 Feb 1;318(3):166-8. PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Further Reading

Papers

  1. . Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002 Nov;59(11):1759-63. PubMed.

Protein Diagram

Primary Papers

  1. . Uncommon polymorphism in the presenilin genes in human familial Alzheimer's disease: not to be mistaken with a pathogenic mutation. Neurosci Lett. 2002 Feb 1;318(3):166-8. PubMed.

Other mutations at this position

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