Mutations

PSEN2 R163H

Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS3
Clinical Phenotype: None
Reference Assembly: GRCh37/hg19
Position: Chr1:227073370 G>A
dbSNP ID: rs778936527
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 6

Findings

This variant was first described in a Swedish family with autosomal-dominant Parkinson's disease due to a mutation in α-synuclein (A53T). The proband was found to be heterozygous for PSEN2 R163H, as was the proband's unaffected mother. The R163H variant was not detected in 170 individuals from the same geographic region (southern Scandinavia) who had been evaluated for suspected hereditary dementia, and the authors suggested it might be a benign polymorphism (Puschmann et al., 2009).

The variant is present in the ExAC variant database (0.00002480 frequency, 3 European individuals, ExAC v.1.0, August 2020) and in the gnomAD variant database (0.00002428 frequency, 6 alleles from European individuals, gnomAD, version 2.1.1, August 2020). 

Neuropathology

Not applicable.

Biological Effect

A cellular assay using mouse neuroblastoma cells expressing the mutant protein showed secretion of similar amounts of Aβ42 and Aβ40 as cells expressing wild-type PSEN2 and no significant alteration of the ratio of Aβ42/Aβ40 (Hsu et al., 2020). Moreover, this residue is not conserved between PSEN1 and PSEN2. However, 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 : 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.  R163H: All 6 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. Puschmann A, Ross OA, Vilariño-Güell C, Lincoln SJ, Kachergus JM, Cobb SA, Lindquist SG, Nielsen JE, Wszolek ZK, Farrer M, Widner H, van Westen D, Hägerström D, Markopoulou K, Chase BA, Nilsson K, Reimer J, Nilsson C. A Swedish family with de novo alpha-synuclein A53T mutation: evidence for early cortical dysfunction. Parkinsonism Relat Disord. 2009 Nov;15(9):627-32. Epub 2009 Jul 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.

External Citations

  1. ExAC v.1.0, August 2020
  2. gnomAD, version 2.1.1, August 2020

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. Puschmann A, Ross OA, Vilariño-Güell C, Lincoln SJ, Kachergus JM, Cobb SA, Lindquist SG, Nielsen JE, Wszolek ZK, Farrer M, Widner H, van Westen D, Hägerström D, Markopoulou K, Chase BA, Nilsson K, Reimer J, Nilsson C. A Swedish family with de novo alpha-synuclein A53T mutation: evidence for early cortical dysfunction. Parkinsonism Relat Disord. 2009 Nov;15(9):627-32. Epub 2009 Jul 25 PubMed.

Other mutations at this position

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