Mutations

PSEN2 T421M

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS3, BP5
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226895494 C>T
Position: (GRCh37/hg19):Chr1:227083195 C>T
dbSNP ID: rs756609078
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 13

Findings

This mutation was found in a screen of Japanese AD patients without a family history of disease and with age at onset under 60 years (Yagi et al., 2014). The proband’s symptoms, described as typical of AD, emerged at age 55.  Genotype information from the proband’s family was unavailable, so it is unclear whether the mutation was inherited or arose de novo. Of note, the proband was homozygous for the APOE4 allele.

The mutation was absent from 112 Japanese controls and from 147 patients with diseases other than AD. Although it was absent from the variant databases dbSNP137 and 1000 genomes in 2014, in 2021, seven heterozygotes, five of Asian ancestry, were reported in the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology
Unknown.

Biological Effect
In mouse neuroblastoma cells lacking endogenous PSEN1 and PSEN2, transfection of this variant resulted in decreased secretion of Aβ40 and Aβ42, with no effect on the Aβ42/Aβ40 ratio, compared with transfection of wildtype PSEN2 (Hsu et al., 2020).

In silico, the variant was predicted to be damaging by three function-prediction algorithms (SIFT, PolyPhen 2, and Pmut; Yagi et al., 2014), and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, also suggesting a deleterious effect (CADD v.1.6, Nov 2021). Moreover, T421 is conserved in vertebrates, and one individual who had a deletion of its PSEN1 homolog, PSEN1 T440del, suffered from early onset parkinsonism and dementia (Ishikawa et al., 2005).

Pathogenicity

Alzheimer's Disease : Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  T421M: Most carriers were of Asian ancestry.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. T421M: Functional effect is not predicted pathogenic since it decreased production of both Aβ40 and Aβ42 without affecting Aβ42/Aβ40.

BP5-P

Variant found in a case with an alternate molecular basis for disease.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022

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References

Mutations Citations

  1. PSEN1 T440del

Paper Citations

  1. Yagi R, Miyamoto R, Morino H, Izumi Y, Kuramochi M, Kurashige T, Maruyama H, Mizuno N, Kurihara H, Kawakami H. Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. Neurobiol Aging. 2014 Jul;35(7):1780.e1-5. Epub 2014 Jan 25 PubMed.
  2. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  3. Ishikawa A, Piao YS, Miyashita A, Kuwano R, Onodera O, Ohtake H, Suzuki M, Nishizawa M, Takahashi H. A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease. Ann Neurol. 2005 Mar;57(3):429-34. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Yagi R, Miyamoto R, Morino H, Izumi Y, Kuramochi M, Kurashige T, Maruyama H, Mizuno N, Kurihara H, Kawakami H. Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. Neurobiol Aging. 2014 Jul;35(7):1780.e1-5. Epub 2014 Jan 25 PubMed.

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