Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3, BS3, BP5
Clinical Phenotype: Late-onset
Position: (GRCh38/hg38):Chr14:73186896 T>C
Position: (GRCh37/hg19):Chr14:73653604 T>C
dbSNP ID: rs63750771
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TTC to TCC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was found in a screen for PSEN1 mutations in an Italian family spanning four generations with several members suffering from late-onset AD (Colacicco et al., 2002). The mutation was identified in only one of three living patients with AD (and two asymptomatic sons of the proband who were younger than the mean age of AD onset). The mutation is unlikely to be a common, non-pathogenic polymorphism of this population because it was absent from 60 individuals with sporadic late-onset AD and 40 normal controls. It was also absent from the gnomAD variant database (gnomAD v2.1.1, June 2021). The authors hypothesize the mutation may be a de novo mutation in the proband, or express incomplete penetrance, causing disease only when combined with other genetic or environmental factors.

Indeed, the authors identified several factors that might affect disease expression in this family. For example, both affected and unaffected individuals in the second generation who were genotyped, including all three patients with AD, carried at least one APOE4 allele. Mean age at onset for the two individuals who were homozygotes was 61, whereas the heterozygote developed symptoms at age 70. In addition, a GG/TT substitution was found in the 3' end of PSEN1 intron 6 of all relatives genotyped in the second and third generations, including affected and unaffected individuals. Levels of estrogen, a hormone reported to be neuroprotective, may also affect disease expression. All affected members of this family were women who experienced precocious menopause without receiving estrogen-replacement therapy.

Biological Effect

Expression of the PSEN1 I439V variant in mouse neuroblastoma cells lacking endogenous PSEN1 and PSEN2 and expressing APP695 (N2A695) resulted in Aβ40 and Aβ42 levels similar to those of cells expressing wild-type PSEN1 (Hsu et al., 2020). The Aβ42/Aβ40 ratio was also unaffected. These authors classified the variant as not pathogenic.

Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the variant's PHRED-scaled CADD score was above 20 suggesting a deleterious effect (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.

PM1-M

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

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.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

BP5-P

Variant found in a case with an alternate molecular basis for disease. F175S: Carrier had LOAD and an APOE4 allele.

	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

Colacicco AM, Panza F, Basile AM, Solfrizzi V, Capurso C, D'Introno A, Torres F, Capurso S, Cozza S, Flora R, Capurso A. F175S change and a novel polymorphism in presenilin-1 gene in late-onset familial Alzheimer's disease. Eur Neurol. 2002;47(4):209-13. 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 F175S

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