Mutations

PSEN2 I368F

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226894036 A>T
Position: (GRCh37/hg19):Chr1:227081737 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to TTC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 12

Findings

This variant was found in a Han Chinese man with Alzheimer’s disease and a family history of dementia (Mao et al., 2021). His age at onset was 60 years. He was homozygous for the APOE3 allele.

This mutation is absent from the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology
Unknown.

Biological Effect
The biological effect of this variant is unknown, but multiple in silico algorithms (SIFT, PolyPhen2, and LRT) predicted a damaging effect (Mao et al., 2021), and its PHRED-scaled CADD score, which integrates diverse information in silico, was above the commonly used deleteriousness threshold of 20 (CADD v.1.6, Oct 2021). Mao and colleagues classified this as a variant of uncertain significance using the ACMG guidelines (Richards et al., 2015).

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.

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

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References

Paper Citations

  1. 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.
  2. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. 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.

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