Mutations

PSEN2 P334R

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: BS1, BS4, BP4
Clinical Phenotype: Alzheimer's Disease, None
Position: (GRCh38/hg38):Chr1:226891773 C>G
Position: (GRCh37/hg19):Chr1:227079474 C>G
dbSNP ID: rs63750207
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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."

Pathogenicity

Alzheimer's Disease : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  P334R: Most carriers were of European ancestry.

BS4-S

Lack of segregation in affected members of a family.

BP4-P

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is less than 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022

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References

Paper Citations

  1. Lleó A, Castellví M, Blesa R, Oliva R. 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. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. 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. Lleó A, Blesa R, Queralt R, Ezquerra M, Molinuevo JL, Peña-Casanova J, Rojo A, Oliva R. 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. Lleó A, Castellví M, Blesa R, Oliva R. 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

View Table

Alzpedia

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