Mutations

PSEN1 G78G

Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: BS1, BP4
Clinical Phenotype: Mild Cognitive Impairment
Position: (GRCh38/hg38):Chr14:73170943 C>T
Position: (GRCh37/hg19):Chr14:73637651 C>T
dbSNP ID: rs143782428
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Silent
Codon Change: GGC to GGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This synonymous variant was found in three members of a family from the Chinese Familial Alzheimer’s Disease Network (Jia et al., 2020). Mean age at disease onset in this familly was 60 years. The proband was a woman who began suffering from mild cognitive impairment at age 66. Two of her nephews carried the mutation and were diagnosed with AD at ages 50 and 53. Both of these carriers had an APOE4/E3 genotype, while the proband was homozygous for APOE3. The father of these two carriers had also been diagnosed with AD, but his genotype was unavailable. Also of note, two sons of another brother of the proband's were healthy at ages 50 and 53, and did not carry the mutation, but were too young to provide evidence of the variant's co-segregation with disease. 

The variant was found in the gnomAD variant database at a frequency of 0.0001804 with an allele count of 49. Most carriers were of European ancestry, with only four of East Asian ancestry. The variant was absent from 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 10.42, 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.  G78G: Most carriers were of European 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.

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.

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