Mutations
PSEN1 V151V
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Overview
Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity
Criteria: PM1, PP3, BP4
Clinical
Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173680 G>T
Position: (GRCh37/hg19):Chr14:73640388 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA
Change: Substitution
Expected RNA
Consequence: Splicing Alteration
Expected Protein
Consequence: Silent
Codon
Change: GTG to GTT
Reference
Isoform: PSEN1 Isoform 1 (467 aa)
Genomic
Region: Exon 5
Findings
This variant was found in three affected siblings of a family in the Chinese Familial Alzheimer’s Disease Network (Jia et al., 2020). The proband was a woman whose AD symptoms started at 73 years of age. Her family included four affected individuals, spanning two generations, with a mean age at onset of 69 years. Two of her brothers were also carriers and suffered from AD symptoms starting at ages 73 and 80. All three of these carriers were homozygous for APOE3. Their deceased father, who was not genotyped, had AD symptoms emerging at 50 years of age. A sister of the proband's who remained cognitively healthy at age 75, did not carry the mutation. Her APOE genotype was APOE3/E2.
The variant was absent from the gnomAD variant database and from the Chinese millionome database.
Neuropathology
Neuropathology data are unavailable.
Biological Effect
The biological effect of this variant is unknown. One in silico algorithm, Human Splicing Finder, predicted it might alter splicing (Jia et al., 2020). However, its PHRED-scaled CADD score was 11.41, well below the threshold of 20 that is commonly used to predict deleteriousness (CADD v1.6, March 2022).
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: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it 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.
PM1-S
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. V151V: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.
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.
BP4-P
Multiple lines of computational evidence suggest no impact on 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 less than 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: 08 Mar 2022
References
Paper Citations
- Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
Further Reading
No Available Further Reading
Protein Diagram
Primary Papers
- Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.
Other mutations at this position
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