Overview

Pathogenicity: Dementia : Not Classified
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226895539 C>T
Position: (GRCh37/hg19):Chr1:227083240 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to CTG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 13

Findings

This variant was identified in a study of 49 Chinese Han patients with dementia onset before age 65 (Han et al., 2020). More than 50 genes associated with dementia, including PSEN2, were screened. The P436L variant was identified in a 56-year-old man who presented with short-term memory impairment, visual deficits, difficulty doing calculations, and mild personality changes at age 52. Similar clinical characteristics were reported for several family members, including the proband’s mother, the mother’s brother, the mother’s sister, as well as the proband’s brother and three sisters. Genetic information for these family members is unavailable.

The variant was absent from 500 healthy Chinese subjects, and reported in three heterozygotes in the gnomAD variant database at a global frequency of 0.000012.

Neuropathology

Neuropathology data are unavailable, but brain MRI of the proband indicated bilateral atrophy of the temporal lobe and hippocampus.

Biological Effect

The biological effects of this variant are unknown, but its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021).

P436L was classified by Han and colleagues as a variant of uncertain significance, following the American College of Medical Genetics and Genomics (ACMG) standards (Richards et al., 2015).

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References

Paper Citations

1. Han LH, Xue YY, Zheng YC, Li XY, Lin RR, Wu ZY, Tao QQ. Genetic Analysis of Chinese Patients with Early-Onset Dementia Using Next-Generation Sequencing. Clin Interv Aging. 2020;15:1831-1839. Epub 2020 Oct 2 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