Mutations

PSEN2 T301M

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: BS1, BS3, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226891293 C>T
Position: (GRCh37/hg19):Chr1:227078994 C>T
dbSNP ID: rs144277432
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 10

Findings

This PSEN2 variant was reported in an individual from the Netherlands who died with a clinical diagnosis of Alzheimer's disease. He first began to experience deficits in short- and long-term memory around age 60. His condition gradually deteriorated and he died approximately 10 years after symptom onset. He had a positive family history of dementia. Several family members were reportedly affected by dementia syndromes; however, details were not reported and segregation with disease was not assessed (Croes et al., 2004).

Sixteen heterozygotes, most of non-Finnish European ancestry, were reported in the gnomAD variant database (v2.1.1, Nov 2021).

Neuropathology

Unknown.

Biological Effect

In vitro, introduction of this mutant form of presenilin-2 did not alter the ratio of secreted Aβ42/Aβ40 (Croes et al., 2004). Moreover, this variant's PHRED-scaled CADD score was 19.9, just below the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, Nov 2021). 

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  T301M: Most carriers are of European ancestry.

BS3-S

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing.

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 20.

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

Paper Citations

  1. Croes EA, Theuns J, Houwing-Duistermaat JJ, Dermaut B, Sleegers K, Roks G, Van den Broeck M, van Harten B, van Swieten JC, Cruts M, Van Broeckhoven C, van Duijn CM. Octapeptide repeat insertions in the prion protein gene and early onset dementia. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1166-70. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Croes EA, Theuns J, Houwing-Duistermaat JJ, Dermaut B, Sleegers K, Roks G, Van den Broeck M, van Harten B, van Swieten JC, Cruts M, Van Broeckhoven C, van Duijn CM. Octapeptide repeat insertions in the prion protein gene and early onset dementia. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1166-70. PubMed.

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