Overview

Pathogenicity: MCI-VaD : Not Classified
Clinical Phenotype: MCI-VaD
Position: (GRCh38/hg38):Chr14:73211883 C>G
Position: (GRCh37/hg19):Chr14:73678591 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TCA to TGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This variant was identified in a 55 year-old Italian man with cognitive decline (Palmieri et al., 2021). His condition was diagnosed as multiple domain amnestic mild cognitive impairment complicated by movement disorders with probable cerebral amyloid angiopathy (CAA). Progression to Alzheimer’s disease (AD) was not confirmed.

Importantly, the proband also carried the PSEN1 R377W variant which disrupts PSEN1 mRNA splicing and has been classified as likely pathogenic.

The S357Ter variant was absent from several variant databases, including gnomAD, 1000 Genomes, and the Exome Sequencing Project (databases accessed in 2018).

Neuropathology
Neuropathology data are unavailable, but an MRI scan revealed multifocal subcortical microhemorrhages mainly in the left posterior hemisphere (Palmieri et al., 2021).

Biological Effect
The biological effect of this variant is unknown, but computer modeling predicted a conformational change with a truncated C-terminus that lacks PSEN1’s last three transmembrane domains (Palmieri et al., 2021). Moreover, two in silico algorithms (PolyPhen2 and SIFT) predicted the variant is deleterious and the PHRED-scaled CADD score, which integrates diverse information, was above 20, suggesting a deleterious effect (CADD v.1.6, Sep 2021).

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References

Mutations Citations

1. PSEN1 R377W

Paper Citations

1. Palmieri I, Valente M, Farina LM, Gana S, Minafra B, Zangaglia R, Pansarasa O, Sproviero D, Costa A, Pacchetti C, Pichiecchio A, Gagliardi S, Cereda C. PSEN1 Compound Heterozygous Mutations Associated with Cerebral Amyloid Angiopathy and Cognitive Decline Phenotype. Int J Mol Sci. 2021 Apr 8;22(8) PubMed.

External Citations

1. CADD v.1.6

Further Reading

No Available Further Reading