Mutations

PSEN2 V393M

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP1, PP3, BS1, BS3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226894111 G>A
Position: (GRCh37/hg19):Chr1:227081812 G>A
dbSNP ID: rs142690225
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 12

Findings

This mutation was first identified in a Danish patient with progressive language and memory disturbances that began at age 50. The proband was diagnosed with Alzheimer's disease due to profound impairment of episodic memory, but also had severe language impairment early in the course of the disease, which is atypical for AD. There was a family history of dementia. The mutation was absent in 13 unaffected family members and in one family member with late-onset AD. It was also absent in 384 normal controls (Lindquist et al., 2008; Lindquist et al., 2009).

The variant was reported in the ExAc (Hsu et al., 2020) and gnomAD (v2.1.1, Nov 2021) variant databases. The latter included 31 heterozygotes, mostly of non-Finnish European ancestry.

Neuropathology

Neuropathological data are unavailable, but FDG-PET imaging of the proband showed bilateral hypometabolism in the parieto-occipital regions (Lindquist et al., 2008).

Biological Effect

Expression of this variant in HEK-293 cells showed no change in secreted Aβ42 or the Aβ42/Aβ40 ratio (Lindquist et al., 2008), and in mouse neuroblastoma cells, both Aβ42 and Aβ40 secretion were reduced, with no change in the Aβ42/Aβ40 ratio (Hsu et al., 2020). In silico analyses, however, predicted the mutation is probably damaging (PolyPhen) and damaging (SIFT), 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, the position is conserved between PSEN1 and PSEN2.

Consistent with Lindquist's and colleagues' suggestion that the variant may be benign, Hsu and colleagues classified it as not pathogenic (Lindquist et al., 2008; Hsu et al., 2020).

 

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.

PP1-P

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion.

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.  V393M: Most carriers were of European ancestry.

BS3-S

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

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. Lindquist SG, Hasholt L, Bahl JM, Heegaard NH, Andersen BB, Nørremølle A, Stokholm J, Schwartz M, Batbayli M, Laursen H, Pardossi-Piquard R, Chen F, St George-Hyslop P, Waldemar G, Nielsen JE. A novel presenilin 2 mutation (V393M) in early-onset dementia with profound language impairment. Eur J Neurol. 2008 Oct;15(10):1135-9. Epub 2008 Aug 22 PubMed.
  2. Lindquist SG, Schwartz M, Batbayli M, Waldemar G, Nielsen JE. Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 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. Lindquist SG, Hasholt L, Bahl JM, Heegaard NH, Andersen BB, Nørremølle A, Stokholm J, Schwartz M, Batbayli M, Laursen H, Pardossi-Piquard R, Chen F, St George-Hyslop P, Waldemar G, Nielsen JE. A novel presenilin 2 mutation (V393M) in early-onset dementia with profound language impairment. Eur J Neurol. 2008 Oct;15(10):1135-9. Epub 2008 Aug 22 PubMed.

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