Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186882_73186883 --->TAT
Position: (GRCh37/hg19):Chr14:73653590_73653591 --->TAT
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Insertion
Expected RNA Consequence: Insertion
Expected Protein Consequence: Insertion
Codon Change: --- to TAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This in-frame insertion of a tyrosine between serine 170 and leucine 171 was found in a U.K. genetic screen of more than 3,000 samples of patients with dementia (Koriath et al., 2018). The mutation carrier was a woman diagnosed with AD, with unknown family history of the disease. Her symptoms emerged at age 38. The mutation was absent from genetic variant databases, including ExAC and gnomAD.

Neuropathology
Unknown

Biological Effect
The biological effect of this mutation is unknown. The site is within PSEN1 transmembrane domain 3, and pathogenic mutations in adjacent amino acids on both sides have been reported. Based on their proposed pathogenicity algorithm, Koriath and colleagues classified the mutation as likely deleterious. Of note, the CADD computational tool which integrates diverse information, yielded a PHRED-scaled score that failed to reach 20, a threshold often used to predict damaging effects (CADD v.1.6, Sep 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. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.

Further Reading

No Available Further Reading