Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PM2, PP3, BP5
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885618 T>C
Position: (GRCh37/hg19):Chr1:227073319 T>C
dbSNP ID: rs1215971988
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to ACC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This variant was found in two Chinese women with Alzheimer's disease. One was a Han Chinese patient with no known family history of the disorder (Mao et al., 2021). Her age at onset was 70 years. The other, who did have a family history of disease, presented with memory loss at age 59 and developed depression and other psychiatric symptoms in subsequent years (Sun et al., 2021). Her diagnosis was AD/frontotemporal dementia. Both carriers had APOE3/E4 genotypes.

A single East Asian heterozygote carrying this mutation was reported in the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology
Unknown.

Biological Effect
In silico algorithms (SIFT, Polyphen, Mutation Taster, M-CAP, and LRT) predicted a damaging or possibly damaging effect for this variant (Mao et al., 2021, Sun et al., 2021) and, consistently, 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). Both Mao et al., and Sun et al. classified this as a variant of uncertain significance using the ACMG guidelines (Richards et al., 2015).

Pathogenicity

Alzheimer's Disease : Uncertain Significance

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.

BP5-P

Variant found in a case with an alternate molecular basis for disease. I146T: Both carriers had an APOE4 allele and relatively late ages of onset.

	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

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.
Sun L, Zhang J, Su N, Zhang S, Yan F, Lin X, Yu J, Li W, Li X, Xiao S. Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing. Front Aging Neurosci. 2021;13:745407. Epub 2021 Oct 14 PubMed.
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.

Mutations

PSEN2 I146T

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