Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PM4, PP3, BP5
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226883912 G>T
Position: (GRCh37/hg19):Chr1:227071613 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: GGA to TGA
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

This variant was found in a Han Chinese man with Alzheimer’s disease and a family history of dementia (Mao et al., 2021). His age at onset was 55 years. He was homozygous for the APOE4 AD risk allele.

This mutation is absent from the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology
Unknown.

Biological Effect
Although the in silico algorithm LTR predicted a neutral effect for this variant (Mao et al., 2021), its PHRED-scaled CADD score, which integrates diverse information in silico, was 40, well above the commonly used deleteriousness threshold of 20 (CADD v.1.6, Oct 2021). Mao and colleagues classified this as a variant of uncertain significance using the ACMG guidelines (Richards et al., 2015).

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.

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.

PM4-M

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.

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.

BP5-P

Variant found in a case with an alternate molecular basis for disease. G117Ter: The reported carrier was homozygous for the APOE4 allele.

	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

Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Román GC, Cui L, Gao J. Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Mutations

PSEN2 G117Ter

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