Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PM5, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226885602 A>G
Position: (GRCh37/hg19):Chr1:227073303 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAC to GAC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This mutation was found in a Han Chinese individual diagnosed with probable AD according to the NINCDS-ADRDA and DSM-IV criteria (Wang et al., 2019). The patient did not have a family history of AD and was APOE4 negative. Age at onset was 59 years.

This mutation was absent from the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology
Unknown

Biological Effect
This mutation was predicted to be damaging by three algorithms with a PHRED CADD score of 24.9. Other mutations at this position, N141I and N141Y, have been linked to AD and N141I produced elevated levels of Aβ42 and increased the Aβ42/Aβ40 ratio (Walker et al., 2005). The mutation was described as definitely pathogenic based on the Guerreiro et al., 2010 guidelines (Wang et al., 2019).

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.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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: 22 Feb 2022

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References

Mutations Citations

Paper Citations

Wang G, Zhang DF, Jiang HY, Fan Y, Ma L, Shen Z, Bi R, Xu M, Tan L, Shan B, Yao YG, Feng T. Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease. J Psychiatr Res. 2019 Jun;113:141-147. Epub 2019 Mar 30 PubMed.
Walker ES, Martinez M, Brunkan AL, Goate A. Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.
Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Mutations

PSEN2 N141D

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