Mutations

PSEN1 P218P

Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: BS1, BP4, BP5
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192749 A>G
Position: (GRCh37/hg19):Chr14:73659457 A>G
dbSNP ID: rs115760359
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Silent
Codon Change: CCA to CCG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This synonymous variant was found in two siblings of a family of the Chinese Familial Alzheimer’s Disease Network (Jia et al., 2020). The family included three affected individuals, spanning two generations, with a mean age at onset of 68 years. The proband had mild cognitive impairment with an age at onset of 68 years. One of her brothers also carried the mutation and developed AD at age 70. Both these carriers were homozygous for APOE4. Of note, a niece and a nephew of both carriers, whose father was affected but not genotyped, were non-carriers and remained cognitively healthy at ages 70 and 72. Both these non-carriers had APOE4/E3 genotypes. 

This variant was found in 67 individuals in the gnomAD variant database, with 66 of them having East Asian ancestry, including one homozygote. It was also reported in the Chinese Millionome database.

Neuropathology
Neuropathology data are unavailable.

Biological Effect
The biological effect of this variant is unknown. One in silico algorithm, Human Splicing Finder, predicted it might alter splicing (Jia et al., 2020). However, its PHRED-scaled CADD score was 4.68, well below the threshold of 20 that is commonly used to predict deleteriousness (CADD v1.6, March 2022).

Pathogenicity

Alzheimer's Disease : Likely 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.  P218P: Most carriers were of East Asian ancestry.

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.

BP5-P

Variant found in a case with an alternate molecular basis for disease. P218P: Both affected carriers had LOAD and were homozygous for the APOE4 allele.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 08 Mar 2022

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References

Paper Citations

  1. Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.

Other mutations at this position

View Table

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