Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
Position: Chr14:73664750 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTT to CTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was identified in a Spanish woman who developed cognitive impairment, including memory loss, as well as gait disruption secondary to spastic paraparesis, at age 40 (Jiménez-Caballero et al., 2008; Gómez-Tortosa et al., 2010). Her brother and mother developed similar symptoms in their late 40s.

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

Neuropathology
Neuropathological data are not available, but MRI of the proband’s brain showed symmetrical cortical and subcortical atrophy, particularly in the frontal lobes, and SPECT revealed bilateral temporal hypoperfusion.

Biological Effects
The biological effects of this variant are unknown, but several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). These authors classified the variant as likely pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

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References

Paper Citations

1. Jiménez Caballero PE, Lladó A, de Diego Boguna C, Martin Correa E, Serviá Candela M, Marsal Alonso C. A novel presenilin 1 mutation (V261L) associated with presenile Alzheimer's disease and spastic paraparesis. Eur J Neurol. 2008 Sep;15(9):991-4. PubMed.
2. Gómez-Tortosa E, Barquero S, Barón M, Gil-Neciga E, Castellanos F, Zurdo M, Manzano S, Muñoz DG, Jiménez-Huete A, Rábano A, Sainz MJ, Guerrero R, Gobernado I, Pérez-Pérez J, Jiménez-Escrig A. Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. J Alzheimers Dis. 2010;19(3):873-84. 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.
4. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

1. gnomAD v2.1.1

Further Reading