Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: PP2, PP3, BS1, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73211867 C>T
Position: (GRCh37/hg19):Chr14:73678575 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This mutation was reported in a Han Chinese family with a history of early-onset AD (Jiang et al., 2014). The reported pedigree shows three affected individuals over four generations. Specifically, the mutation was detected in two individuals, one affected and one unaffected at the age of 56. Therefore, the mutation does not currently segregate with disease in this family, although the unaffected mutation carrier may be presymptomatic, as onset in the family ranged from 56 to 62 years of age. Disease in this family is characterized by psychiatric and behavioral symptoms in addition to memory loss. The disease course was quite protracted, ranging from 12 to 22 years after onset.

The allele count and frequency of this variant in the gnomAD database were 12 and 0.0043 percent, respectively, suggesting less than 10 percent penetrance (Koriath et al., 2018).

Neuropathology

Unknown. Imaging showed global cerebral atrophy.

Biological Effect

In vitro experiments with isolated proteins revealed that production of Aβ42 and Aβ40 were reduced compared with wildtype PSEN1, and the Aβ42/Aβ40 ratio was similar (Sun et al., 2017). A cellular assay using mouse neuroblastoma cells expressing the mutant protein also showed no significant effect on the Aβ42/Aβ40 ratio and, in this case, secretion of Aβ42 and Aβ40 was similar to that of cells expressing wild-type PSEN1 (Hsu et al., 2020).

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021), although the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score, above 20 (CADD v.1.6, Sep 2021).

Koriath and colleagues described the variant as "most likely benign" or causing an "only small increase in risk" (Koriath et al., 2018)

Pathogenicity

Alzheimer's Disease : Likely Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.

BS3-P

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. R352C: Aβ42/Aβ40 ratio unchanged and production of both these peptides decreased, but other Ab peptides were not examined.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 22 Feb 2022

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References

Paper Citations

Jiang HY, Li GD, Dai SX, Bi R, Zhang DF, Li ZF, Xu XF, Zhou TC, Yu L, Yao YG. Identification of PSEN1 mutations p.M233L and p.R352C in Han Chinese families with early-onset familial Alzheimer's disease. Neurobiol Aging. 2015 Mar;36(3):1602.e3-6. Epub 2014 Dec 18 PubMed.
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.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
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.

Mutations

PSEN1 R352C

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