Overview

Pathogenicity: bvFTD : Not Classified
Clinical Phenotype: bvFTD
Position: (GRCh38/hg38):Chr1:226894097 C>T
Position: (GRCh37/hg19):Chr1:227081798 C>T
dbSNP ID: rs143549266
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to ATG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 12

Findings

This variant was found in a screen of 16 dementia genes by whole-exome sequencing in Spanish patients with early onset dementia (Ramos-Campoy et al., 2020).  The carrier was diagnosed with behavioral variant frontal temporal dementia with age at onset of 45 years. They were homozygous for the APOE3 allele, and had no family history of dementia.

Thirty-two heterozygotes were reported in the gnomAD variant database, 31 with European ancestry. The global frequency was 0.0001132 (gnomAD v2.1.1, Oct 2021).

Neuropathology
Neuropathological data are unavailable. The reported carrier’s levels of cerebrospinal spinal fluid biomarkers, Aβ42, tau, and phospho-tau, were not consistent with AD (Ramos-Campoy et al., 2020). 

Biological Effect
The biological effect of this variant is unknown, but all eight of the in silico algorithms applied (SIFT, Polyphen-2, LRT, Mutation Taster, Mutation Assesor, FATHMM, Radial SVM, and LR) predicted a damaging effect (Ramos-Campoy et al., 2020). Consistently, its PHRED-scaled CADD score (29), which integrates diverse information in silico, was above the commonly used deleteriousness threshold of 20. Ramos-Campoy and colleagues classified it as a variant of uncertain significance according to Richards et al., 2015 (Ramos-Campoy et al., 2020).

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References

Paper Citations

1. Ramos-Campoy O, Antonell A, Falgàs N, Balasa M, Borrego-Écija S, Rodríguez-Santiago B, Datta D, Armengol L, Fernández-Villullas G, Bosch B, Olives J, Muñoz-García C, Castellví M, Tort-Merino A, Sánchez-Valle R, Lladó A. Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants. Neurobiol Aging. 2020 Sep;93:e1-e9. Epub 2020 Feb 18 PubMed.
2. 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.

Further Reading

No Available Further Reading