Mutations

PSEN2 P334A

Overview

Pathogenicity: Alzheimer's Disease : Benign
Clinical Phenotype: Alzheimer's Disease, None
Reference Assembly: GRCh37/hg19
Position: Chr1:227079473 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCT to GCT
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 11

Findings

This variant in PSEN2 was identified in one of 184 probands representing Caribbean Hispanic families affected by familial Alzheimer’s disease (Lee et al., 2014). The mutation was also observed in two of 12 unaffected family members, and therefore does not appear to segregate with disease. The proband met NINCDS-ADRDA criteria for probable AD, but further clinical details were not reported. Note, this variant was reported as PSEN2 P301A, but the nucleotide change observed corresponds to P334A in the canonical isoform of presenilin-2.

Seven heterozygotes were reported in the gnomAD variant database, including five having Latino/Admixed American ancestry (v2.1.1, Nov 2021). 

Neuropathology

Not applicable.

Biological Effect

Mouse neuroblastoma cells transfected with this variant and lacking endogenous PSEN1 and PSEN2 secreted moderately less Aβ40 than similar cells expressing wildtype PSEN2, but their Aβ42/Aβ40 ratio was not significantly different from controls (Hsu et al., 2020). Moreover, position P334 is not conserved between PSEN1 and PSEN2, and this variant's 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. . Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014 Sep;2(5):430-7. Epub 2014 Jun 4 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

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014 Sep;2(5):430-7. Epub 2014 Jun 4 PubMed.

Other mutations at this position

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