Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: None
Reference Assembly: GRCh37/hg19
Position: Chr14:73659375 T>C
dbSNP ID: rs112451138
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to GCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in an individual from the African San population (Guerreiro et al. 2010).  No neurodegenerative phenotype was reported. It was absent from two exome variant databases, EVS and ExAC (Hsu et al., 2020).

Neuropathology
Unknown

Biological effect
Mouse neuroblastoma cells expressing this variant secreted approximately half the amount of Aβ42 as cells expressing wild-type PSEN1 (Hsu et al., 2020). Secretion of Aβ40 was also decreased, but this reduction did not reach significance, nor did reduction in the Aβ42/Aβ40 ratio.

The V191 position is conserved between PSEN1 and PSEN2 and, although  some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Hsu et al., 2020, Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Hsu et al. classified the mutation as not pathogenic and possibly protective, given this variant's reduction of Aβ42 secretion in a cell assay (Hsu et al., 2020).

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References

Paper Citations

1. 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.
2. 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.
3. 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.

External Citations

1. CADD v.1.6

Further Reading

No Available Further Reading