Mutations
PSEN2 N141S
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Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PM2, PM5, PP3
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885603 A>G
Position: (GRCh37/hg19):Chr1:227073304 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Substitution
Expected Protein
Consequence: Missense
Codon
Change: AAC to AGC
Reference
Isoform: PSEN2 Isoform 1 (448 aa)
Genomic
Region: Exon 6
Findings
This variant was found in a Han Chinese woman with Alzheimer’s disease and a family history of dementia (Mao et al., 2021). Her age at onset was 52 years. She had an APOE3/E4 genotype.
This mutation is absent from the gnomAD variant database (v2.1.1, Oct 2021).
Neuropathology
Unknown.
Biological Effect
Multiple in silico algorithms (SIFT, Polyphen, LTR) predicted this variant is damaging or possibly damaging (Mao et al., 2021) and, consistently, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (CADD v.1.6, Oct 2021). Mao and colleagues classified it as likely pathogenic. Of note, the first pathogenic mutation described in PSEN2 maps to the same residue, PSEN2 N141I (Volga German).
Pathogenicity
Alzheimer's Disease : Not Classified*
*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.
This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.
PM2-M
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.
PM5-M
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
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.
| 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
References
Paper Citations
- Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Román GC, Cui L, Gao J. Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
Other Citations
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Román GC, Cui L, Gao J. Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
Other mutations at this position
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