Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr1:227076598 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGG to GTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Spanish family affected by late-onset Alzheimer’s disease (Marín-Muñoz et al., 2016). There were four affected family members over two generations: three siblings and their maternal uncle. The mother is a presumed carrier of the mutation, but was asymptomatic when she died from other causes at age 54. Age of onset in this family ranged from age 60 to age 65 with death in the mid-70s. Symptoms were very typical of AD with progressive memory decline, sometimes with depression and anxiety. Parkinsonism, significant behavioral or psychiatric symptoms, and seizures were not characteristic of the disease in this family. The mutation  was found in the two affected siblings available for testing.

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

Neuropathology

Neuropathology consistent with a diagnosis of AD was observed in the brain of one of the affected mutation carriers (Marín-Muñoz et al., 2016). He also had some mild amyloid angiopathy and some Lewy bodies in the amygdala.

Biological Effect

Unknown. This mutation was predicted to be pathogenic in silico by PolyPhen2 (Marín-Muñoz et al., 2016) and, consistently, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (CADD v.1.6, Nov 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: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it 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. Marín-Muñoz J, Noguera-Perea MF, Gómez-Tortosa E, López-Motos D, Antequera-Torres M, Martínez-Herrada B, Manzanares-Sánchez S, Vivancos-Moreau L, Legaz-García A, Rábano-Gutiérrez Del Arroyo A, Antúnez-Almagro C. Novel Mutation (Gly212Val) in the PS2 Gene Associated with Early-Onset Familial Alzheimer's Disease. J Alzheimers Dis. 2016 Apr 25;53(1):73-8. PubMed.

Further Reading

No Available Further Reading