Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640359 G>A
dbSNP ID: rs63751037
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTC to ATC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was found in a U.K. genetic screen of more than 3,000 samples of patients with dementia (Koriath et al., 2018). The carrier was a man diagnosed with AD who had one known relative with early onset dementia. Age at onset was 54 years. The mutation was absent from genetic variant databases, including ExAC, EVS, 1000G, and gnomAD.

Neuropathology
Unknown

Biological Effect
The biological effect of this mutation is unknown. However, the affected site is highly conserved across species and in PSEN2. In addition, another pathogenic mutation has been reported at this site, as well as mutations in neighboring residues aligned along the helical face of the second transmembrane domain. Based on their proposed pathogenicity algorithm, Koriath and colleagues classified the mutation as deleterious.

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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