Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP3, BS2
Clinical Phenotype: Alzheimer's Disease, None
Position: (GRCh38/hg38):Chr1:226888955 A>T
Position: (GRCh37/hg19):Chr1:227076666 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to TTC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8

Findings

This variant in PSEN2 was identified in one of 183 probands representing Caribbean Hispanic families affected by familial Alzheimer’s disease. The I235F variant was also observed in two of 11 unaffected family members. Whether this observation can be considered evidence against cosegregation is uncertain because the unaffected carriers' ages were not reported. Moreover, evidence for linkage was weak, but associations in a joint linkage and association analysis were reported as significant.The proband met NINCDS-ADRDA criteria for probable AD, but further clinical details were not reported (Lee et al., 2014).

The variant is absent from the ExAC and EVS variant databases (Hsu et al., 2020).

Neuropathology

Unknown.

Biological Effect

Mouse neuroblastoma cells transfected with the variant revealed an approximately 2-fold increase in the Aβ42/Aβ40 ratio compared with cells transfected with wildtype PSEN2 (Hsu et al., 2020). In addition, in silico algorithms 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, consistent with a deleterious effect (CADD v.1.6, Nov 2021). Residue I235 is conserved between PSEN1 and PSEN2. Based on their pathogenicity guidelines, Hsu and colleagues classified I235F as probably pathogenic.

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.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

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.

BS2-P

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age. I235F: Two unaffected carriers were reported, but their ages are unknown.

	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

Lee JH, Kahn A, Cheng R, Reitz C, Vardarajan B, Lantigua R, Medrano M, Jiménez-Velázquez IZ, Williamson J, Nagy P, Mayeux R. Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med. 2014 Sep;2(5):430-7. Epub 2014 Jun 4 PubMed.
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.

Mutations

PSEN2 I235F

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