Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226883799 T>C
Position: (GRCh37/hg19):Chr1:227071500 T>C
dbSNP ID: rs760961297
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to CCG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

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 had an AD phenotype with age at onset of 52 years, homozygosity of the APOE3 allele, and no family history of dementia.

Three European heterozygotes were reported in the gnomAD variant database, with a global frequency of 0.00001193 (v2.1.1, Oct 2021).

Neuropathology
Neuropathological data are unavailable, but the reported carrier’s levels of cerebrospinal spinal fluid biomarkers, Aβ42, tau, and phospho-tau, were consistent with AD (Ramos-Campoy et al., 2020). 

Biological Effect
The biological effect of this variant is unknown, but five of eight in silico algorithms (LRT, Mutation Taster, FATHMM, RadialSVM, LR) predicted it has a deleterious effect and its PHRED-scaled CADD score, which integrates diverse information in silico, was also consistent with a damaging effect (22.9). Ramos-Campoy and colleagues classified it as a variant of uncertain significance according to Richards et al., 2015 (Ramos-Campoy et al., 2020).

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: only one affected carrier has been reported without co-segregation data, and the variant 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

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