Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192711 G>C
Position: (GRCh37/hg19):Chr14:73659419 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGT to CGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was identified in a Swedish woman with Alzheimer’s disease (Libard et al., 2022). The patient’s first symptoms, anxiety, impaired attention, and short-term memory loss, emerged at age 54 and were followed by progressive cognitive decline over nearly two decades, including episodic memory impairment and difficulty with calculations. Her anxiety, irritability, and mood swings also worsened. She died at age 73. Her mother had also been diagnosed with early onset AD and had similar symptoms beginning at age 60.

Sequencing of the proband’s PSEN1, PSEN2, APP, and APOE genes revealed the G206R mutation with an APOE3/E3 genotype.

The variant was absent from the two public variant databases, NCBI SNP (dbSNP) and gnomAD.

Neuropathology
Neuropathology of the proband was consistent with AD, but more extensive than that of an age- and gender-matched control with sporadic AD (Libard et al., 2022). Notably, the proband had end-stage TDP-43 pathology, which was only moderate in the sporadic AD case, and severe α-synuclein pathology which was absent in the sporadic AD subject. The mutation carrier also had pronounced neuroinflammation.

Also of note, at age 60, the proband had a CT scan which revealed mild cortical atrophy and at age 62, a PET scan showed marked hypometabolism in the parietal lobes and the posterior temporal lobe, with moderate hypometabolism in the frontal lobes, especially on the right side.

Biological Effect
The biological effect of this variant is unknown, but several pathogenic substitutions of G206 have been identified. Moreover, the variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was 29.2, suggesting a damaging effect (CADD v.1.6, Jan 2023).

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. Libard S, Giedraitis V, Kilander L, Ingelsson M, Alafuzoff I. Mixed Pathologies in a Subject with a Novel PSEN1 G206R Mutation. J Alzheimers Dis. 2022;90(4):1601-1614. PubMed.

Further Reading

No Available Further Reading