Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659468 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAG to CCG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was first identified in a woman who developed memory impairment with word-finding difficulties and dyscalculia at age 46 (Scahill et al., 2013; Ryan et al., 2016). She was adopted and had no information about her birth family. The mutation was also reported in an individual who developed dementia at age 49 (Koriath et al., 2018). The mutation was absent from 100 healthy individuals (Ryan et al, 2016), and from the ExAC exome database (Koriath et al., 2018).

Neuropathology

Unknown

Biological Effect

The residue is conserved between species and PSENs. Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) predicted this variant is damaging (Xiao et al., 2021, Ryan et al., 2016). Ryan and colleagues classified it as probably pathogenic.

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References

Paper Citations

1. Scahill RI, Ridgway GR, Bartlett JW, Barnes J, Ryan NS, Mead S, Beck J, Clarkson MJ, Crutch SJ, Schott JM, Ourselin S, Warren JD, Hardy J, Rossor MN, Fox NC. Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations. J Alzheimers Dis. 2013 Jan 1;35(1):199-212. PubMed.
2. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
3. 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.
4. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Further Reading

No Available Further Reading