Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PM6, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659420 G>T
dbSNP ID: rs63750082
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGT to GTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation has been reported in the proband of a family with multigenerational, early onset Alzheimer’s disease. The reported pedigree shows four affected individuals over three generations. The proband, EN, developed disorientation at age 30 with insidious onset of memory impairment. He died at 39 with a diagnosis of AD. His mother died of autopsy-confirmed AD at age 42, with onset in her early 30s. Her first symptoms were confusion, handwriting changes, word-finding problems, short-term memory loss, and anger. She later developed severe loss of language and motor skills, disorientation, seizures, and blindness. The proband’s maternal grandfather died of an unspecified dementia in his early 40s. The G206V mutation was hypothesized to be pathogenic, but confirmation was not possible in this family as the other affected family members were deceased (Goldman et al., 2002).

The mutation was also found in a Chinese AD patient who experienced progressive memory loss combined with irritability and anxiety, starting at age 30 (Li et al., 2019). No additional members of his family had AD and analyses of DNA microsatellite markers suggested the mutation occurred de novo. The mutation was absent from 200 Chinese healthy controls and two genetic variant databases (ExAC and 1000 Genomes).

Neuropathology

Unknown. In one case, MRI revealed mild atrophy of the brain with normal temporal lobes (Goldman et al., 2002), but in another, it showed temporal and hippocampal atrophy (Li et al., 2019).

Biological Effect

In a cell-based assay, this variant increased total Aβ production and Aβ42 in particular, while decreasing production of Aβ43, Aβ40, and Aβ38 (Kakuda et al., 2021). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in this residue could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate binding (Zhou et al., 2019; Jan 2019 news).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic

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.

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. G206V: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PM6-M

Assumed de novo, but without confirmation of paternity and maternity.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

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: 04 Mar 2022

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References

News Citations

Paper Citations

Goldman JS, Reed B, Gearhart R, Kramer JH, Miller BL. Very early-onset familial Alzheimer's disease: a novel presenilin 1 mutation. Int J Geriatr Psychiatry. 2002 Jul;17(7):649-51. PubMed.
Li YS, Yang ZH, Zhang Y, Yang J, Shang DD, Zhang SY, Wu J, Ji Y, Zhao L, Shi CH, Xu YM. Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging Dis. 2019 Aug;10(4):908-914. PubMed.
Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Mutations

PSEN1 G206V

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