Mutations

PSEN2 V101M

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226883864 G>A
Position: (GRCh37/hg19):Chr1:227071565 G>A
dbSNP ID: NA
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 5

Findings

This variant was detected in an individual with apparently sporadic AD (Frigerio et al., 2015). There was no family history of dementia. Other than the diagnosis, clinical details related to this individual were not reported. 

Three heterozygote carriers of this variant, two of European ancestry and one of African ancestry, were reported in the gnomAD variant database (v2.1.1, Nov 2021). The global frequency was 0.00001194.

Neuropathology

Unknown.

Biological Effect

The biological effect of this variant is unknown, but the residue is conserved between PSEN1 and PSEN2 (Hsu et al., 2020). Moreover, in silico, this variant was predicted to be probably damaging by PolyPhen-2, and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Nov 2021) .

 

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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.

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. 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.

Other Citations

  1. Frigerio et al., 2015

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, Voet T, De Strooper B. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimers Dement. 2015 Apr 29; PubMed.

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