Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Parkinsonism
Position: (GRCh38/hg38):Chr14:73192771 C>G
Position: (GRCh37/hg19):Chr14:73659479 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This variant was identified in an Italian Caucasian man diagnosed with early onset Alzheimer’s disease (AD) with parkinsonism (Zilioli et al., 2023). He was diagnosed at age 52, with progressive memory loss evident at age 50 and bradykinesia and left-hand tremor at age 51. He also suffered from visuospatial impairment and depression. His father had dementia at age 50 and his brother committed suicide at that age. The L226V variant was identified after targeted sequencing of dementia-associated genes DCTN1, MAPT, GRN, PSEN-1, PSEN-2, and TARDBP.

This variant was absent from the gnomAD variant database (v.4.0.0, Jan 2024).

Neuropathology
Neuropathological data are unavailable, but brain imaging of the proband revealed a posterior gradient of atrophy, white matter alterations in cortical and subcortical regions, and hypoperfusion in the right temporal, parietal, and occipital lobes, as well as hippocampal atrophy (Zilioli et al., 2023). In addition, Aβ42 levels and the Aβ42/Aβ40 ratio in cerebrospinal fluid were consistent with AD pathology, although tau and phospho-tau levels were normal. 

Biological Effect
The biological effect of this variant is unknown, but two other variants at this location, L226F and L226R, have been classified as pathogenic. Also,  its location is consistent with the helical alignment of pathogenic mutations in transmembrane domain 5 (Coleman et al., 2004) and L226V’s PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (28), suggesting a deleterious effect (CADD v.1.7, Jan 2024).

Zilioli and colleagues classified the variant as likely pathogenic based on the ACMG-AMP (Richards et al., 2015) and Guerreiro et al.’s guidelines (Guerreiro et al., 2010).

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

Mutations Citations

1. PSEN1 L226F
2. PSEN1 L226R

Paper Citations

1. Zilioli A, Misirocchi F, Pancaldi B, Mutti C, Ganazzoli C, Florindo I, Spallazzi M. A Novel Presenilin-1 Mutation (Leu226Val) In Early Onset Alzheimer's Disease With Parkinsonism. Can J Neurol Sci. 2023 Sep 11;:1-4. PubMed.
2. Coleman P, Kurlan R, Crook R, Werner J, Hardy J. A new presenilin Alzheimer's disease case confirms the helical alignment of pathogenic mutations in transmembrane domain 5. Neurosci Lett. 2004 Jul 8;364(3):139-40. PubMed.
3. 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.

External Citations

1. Richards et al., 2015

Further Reading

No Available Further Reading