Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3
Position: (GRCh38/hg38):Chr14:73173634 C>T
Position: (GRCh37/hg19):Chr14:73640342 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to GTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This variant was found in a Chinese man diagnosed with sporadic early onset Alzheimer’s disease (Li et al., 2021). It was identified by whole-exome sequencing of 35 dementia-associated genes. In addition to the A136V substitution, the man also carried DCTN1 E875K, a variant in the dynactin-1 gene. The man first complained of memory impairment and apathy at age 50, and by 53 was experiencing disorientation, followed by more severe memory loss and language disruption at age 54. Based on clinical examination, brain imaging, and cerebrospinal fluid biomarkers, he was diagnosed with sporadic early onset AD with an age at onset of 56 years. He had an APOE E2/E4 genotype.

The variant was absent from several variant databases, including the Exome Sequencing Project, 1000 Genomes Project, ExAC, and gnomAD.

Neuropathology
Neuropathological data are unavailable, but an MRI brain scan revealed bilateral hippocampi atrophy and FDG-PET showed substantial hypometabolism in bilateral temporal, parietal, and occipital cortices (Li et al., 2021).  Moreover, the ratio of Aβ42 to total tau in cerebrospinal fluid was elevated, consistent with AD neuropathology.

Biological Effect
The biological effect of this variant is unknown, but in silico algorithms (Polyphen2 and SIFT) predicted it to be deleterious (Li et al, 2021). Moreover, the variant's PHRED-scaled CADD score was above 20, suggesting a damaging effect (v1.6, 2021).

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.

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References

Paper Citations

1. Li XY, Cui Y, Jing D, Xie K, Zhong X, Kong Y, Wang Y, Chu M, Wang C, Wu L. Novel PSEN1 and PSEN2 Mutations Identified in Sporadic Early-onset Alzheimer Disease and Posterior Cortical Atrophy. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):208-213. PubMed.

Further Reading

No Available Further Reading