Mutations

PSEN1 N32N

Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: BS1, BP7, BP4
Clinical Phenotype: Alzheimer's Disease, None
Position: (GRCh38/hg38):Chr14:73170805 T>C
Position: (GRCh37/hg19):Chr14:73637513 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Silent
Codon Change: AAT to AAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This is a silent polymorphism, considered most likely not pathogenic. It was first reported in a Caucasian woman from northern Italy who was diagnosed with probable Alzheimer’s disease according to NINCDS-ADRDA criteria. She experienced symptom onset at age 81 and did not have a family history of dementia, consistent with sporadic AD. Segregation analysis was not possible in this case. The T>C polymorphism was absent in 114 healthy unrelated individuals, but the reporting authors indicated that the polymorphism was most likely not pathogenic due to the fact that it was a synonymous change and in a position not conserved in PSEN2 or in other species (Scacchi et al., 2007).

Consistent with this proposal, the variant was described as "most likely benign" or causing an "only small increase in risk" based on its allele count (12) and frequency (0.0043 percent) in the gnomAD variant database (Koriath et al., 2018). The penetrance was calculated to be two percent or less. Hsu and colleagues classified this variant as "not pathogenic" (Hsu et al., 2020)

Neuropathology

Unknown.

Biological Effect

Unknown.

Pathogenicity

Alzheimer's Disease : Likely 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.  N32N: Most carriers were of European ancestry.

BP7-P

A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.

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. Scacchi R, Gambina G, Moretto G, Corbo RM. A mutation screening by DHPLC of PSEN1 and APP genes reveals no significant variation associated with the sporadic late-onset form of Alzheimer's disease. Neurosci Lett. 2007 May 18;418(3):282-5. Epub 2007 Mar 21 PubMed.
  2. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
  3. 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Scacchi R, Gambina G, Moretto G, Corbo RM. A mutation screening by DHPLC of PSEN1 and APP genes reveals no significant variation associated with the sporadic late-onset form of Alzheimer's disease. Neurosci Lett. 2007 May 18;418(3):282-5. Epub 2007 Mar 21 PubMed.

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