Mutations

PSEN1 K395I

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73683888 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAA to ATA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This variant was found in a Brazilian family spanning three generations with early onset Alzheimer’s disease (Takada et al., 2022). Mean age at onset was 51 years. The proband first developed episodic memory loss at 51 followed by anomia, geographic disorientation, and apathy. Earlier, when the proband was in their 30s, they developed postural tremor of both hands and had mild rigidity in their upper right arm.

One of the proband’s parents had AD with parkinsonism which started at age 55 and their grandparent had similar symptoms with an age at onset of 60 years. In addition, one of the proband’s siblings developed AD at age 55.

The variant was identified in the proband and the affected sibling but was absent from an older sibling who was asymptomatic at age 59.

The variant was absent from the variant databases gnomAD and the exome variant server, and was not reported in the ClinVar database.

Neuropathology
Neuropathological data are unavailable. No abnormalities were detected in an early MRI scan of the proband’s brain, nor in an electroencephalogram (Takada et al., 2022).

Biological Effect
An assay using neuroblastoma N2A cells lacking endogenous presenilin genes and expressing the K395I mutation revealed a moderate increase in the Aβ42/Aβ40 ratio and a substantial decrease in both Aβ42 and Aβ40 levels (Takada et al., 2022).

L395 is highly conserved across species. Moreover, K395I’s PHRED-scaled CADD score (31), which integrates diverse information in silico, was above 20, suggesting a deleterious effect. The authors classified this variant as pathogenic based on the algorithm described by Hsu et al., 2018.

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

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

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. K395I: Moderately increased Aβ42/Aβ40 ratio and substantially decreased both Aβ42 and Aβ40 levels.

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. K395I: Variant located at edge of mutational hot spot.

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.

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

Last Updated: 29 Dec 2022

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References

Paper Citations

  1. Takada LT, Aláez-Verson C, Burgute BD, Nitrini R, Sosa AL, Castilhos RM, Chaves MF, Longoria EM, Carrillo-Sánchez K, Brucki SM, Flores-Lagunes LL, Molina C, Olivares MJ, Ziegemeier E, Petranek J, Goate AM, Cruchaga C, Renton AE, Fernández MV, Day GS, McDade E, Bateman RJ, Karch CM, Llibre-Guerra JJ, Dominantly Inherited Alzheimer Network. Discovery and validation of dominantly inherited Alzheimer's disease mutations in populations from Latin America. Alzheimers Res Ther. 2022 Aug 5;14(1):108. PubMed.
  2. Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TL, Goate AM, Cruchaga C, Bateman RJ, Dominantly Inherited Alzheimer Network (DIAN), Karch CM. Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Takada LT, Aláez-Verson C, Burgute BD, Nitrini R, Sosa AL, Castilhos RM, Chaves MF, Longoria EM, Carrillo-Sánchez K, Brucki SM, Flores-Lagunes LL, Molina C, Olivares MJ, Ziegemeier E, Petranek J, Goate AM, Cruchaga C, Renton AE, Fernández MV, Day GS, McDade E, Bateman RJ, Karch CM, Llibre-Guerra JJ, Dominantly Inherited Alzheimer Network. Discovery and validation of dominantly inherited Alzheimer's disease mutations in populations from Latin America. Alzheimers Res Ther. 2022 Aug 5;14(1):108. PubMed.

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