Mutations

PSEN2 A377V

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2
Clinical Phenotype: Alzheimer's Disease, None
Position: (GRCh38/hg38):Chr1:226894064 C>T
Position: (GRCh37/hg19):Chr1:227081765 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to GTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 12

Findings

This variant in PSEN2 was identified in one out 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 nine 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 A344V, but the nucleotide change observed corresponds to A377V in the reference isoform of presenilin-2.

Twelve heterozygotes were reported in the gnomAD variant database. Although most (eight) were of non-Finnish European ancestry, two were members of the Latino/Admixed American population (gnomAD v2.1.1, Nov 2021).

Neuropathology

Not applicable.

Biological Effect

The biological effects of this variant are unknown, but its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

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.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the 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 greater than or equal to 20.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  A377V: Most carriers were of European 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.

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. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. 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.

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