Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Dementia with Lewy Bodies : Not Classified, Frontotemporal Dementia : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Dementia with Lewy Bodies, Frontotemporal Dementia, Myoclonus
Position: (GRCh38/hg38):Chr14:73173621 T>G
Position: (GRCh37/hg19):Chr14:73640329 T>G
dbSNP ID: rs200937800
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was identified in a retrospective analysis of genotypic and phenotypic data from individuals with autosomal-dominant familial AD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, U.K (Ryan et al., 2016).  The carrier of this mutation presented with a dementia with Lewy bodies phenotype. He developed memory impairment at age 59 with early symptoms of visual dysfunction and difficulty learning new tasks. He subsequently developed visual hallucinations, paranoia, and dyspraxia, He also developed myoclonic jerks, bradykinesia, and increased limb tone throughout. His family included three affected individuals with ages of disease onset ranging from 58-60 years.

In addition to the S132A mutation, the patient also had an intronic variant in the MAPT gene (NM_005910・5: rs11872014), but it was considered unlikely to be pathogenic given its presence in an elderly healthy control. Also, the MAPT variant has been described hundreds of times in the Exome Aggregate Consortium (ExAC) dataset. 

The S132A mutation was also reported in two individuals in a screen of 3241 U.K. patients with dementia; one case diagnosed with early onset AD and the other with early onset frontotemporal dementia (Koriath et al., 2018). It is uncertain if the patient with AD was the same individual as previously reported by Ryan and colleagues (Ryan et al., 2016).

The mutation was found in one individual of European ancestry in the ExAC dataset, but was absent from 100 healthy, white controls (Ryan et al., 2016). It was classified as likely deleterious and most likely fully penetrant, with an allele count of one and a frequency of 0.000004 in the gnomAD variant database (Koriath et al., 2018). 

Neuropathology

The proband had AD pathology with severe neocortical Lewy body disease identified post mortem at 70 years of age. At 64, an MRI scan revealed widespread atrophy (Ryan et al., 2016).

Biological Effect

The biological effect of this variant is unknown. However, the affected amino acid is conserved between PSENs and located close to the second transmembrane domain (Ryan et al., 2016). Moreover, although some in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve) yielded conflicting results (Ryan et al., 2016, Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). Ryan and colleagues classified it as possibly pathogenic.

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because it is unclear if more than one affected carrier has been reported—cosegregation data are lacking—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. 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.
2. 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.
3. 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.

External Citations

1. CADD v.1.6

Further Reading

No Available Further Reading