Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: BS1, BS2, BS3, BP4
Clinical Phenotype: Alzheimer's Disease, None
Reference Assembly: GRCh37/hg19
Position: Chr1:227079473 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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."

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. P334A: Most carriers were of Latino/Admixed American ancestry.

BS2-S

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

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

Lee JH, Kahn A, Cheng R, Reitz C, Vardarajan B, Lantigua R, Medrano M, Jiménez-Velázquez IZ, Williamson J, Nagy P, Mayeux R. Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014 Sep;2(5):430-7. Epub 2014 Jun 4 PubMed.
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.

Mutations

PSEN2 P334A

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