Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73217129 G>T
Position: (GRCh37/hg19):Chr14:73683837 G>T
dbSNP ID: rs63750323
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGA to GTA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was originally identified in a family from the United Kingdom. The family, identified as Family 134, had 13 members affected by Alzheimer’s disease over three generations. The average age of onset was 43 (range: 41-49 years). The mutation was found in three affected family members and was described as segregating with disease but no unaffected, non-carriers were reported (Janssen et al., 2003).

This mutation was later found in a Hispanic woman from Florida with early onset AD. She had a positive family history but details were not reported. Age of onset is unknown; she died at age 51 (Ravenscroft et al., 2016).

The mutation was also identified in two members of a Canadian family diagnosed with probable and possible corticobasal syndrome (Lam et al., 2017). The age at onset for these patients was 43 and 45 years, respectively. Initial symptoms included inattention, memory impairment, personality change, and in one case, depressed mood.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology

Some affected members of Family 134 had autopsy-confirmed AD (Janssen et al., 2003). MRI scans of the Canadian patients revealed moderate atrophy of the side of the brain contralateral to their affected hemibody in one case, and generalized atrophy in the other (Lam et al., 2017). SPECT showed hypoperfusion of contralateral temporal and parietal regions in one case, and frontal cortex in the other.

Biological Effect

In vitro assays with isolated proteins indicate this mutation dramatically decreases Aβ42 and Aβ40 production (Sun et al., 2017). The levels of Aβ40 were undetectable. 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, Lam et al., 2017).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that G378 forms part of one of two PSEN1 β-strands induced by APP binding. These strands, together with an APP β-strand, form a hybrid, three-stranded β–sheet that appears to be indispensable for cleavage (Zhou et al., 2019; Jan 2019 news).

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. G378V: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

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. G378V: 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.

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: 22 Feb 2022

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References

News Citations

Paper Citations

Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
Ravenscroft TA, Pottier C, Murray ME, Baker M, Christopher E, Levitch D, Brown PH, Barker W, Duara R, Greig-Custo M, Betancourt A, English M, Sun X, Ertekin-Taner N, Graff-Radford NR, Dickson DW, Rademakers R. The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset Alzheimer's disease in Hispanics in Florida. Am J Neurodegener Dis. 2016;5(1):94-101. Epub 2016 Mar 1 PubMed.
Lam B, Khan A, Keith J, Rogaeva E, Bilbao J, St George-Hyslop P, Ghani M, Freedman M, Stuss DT, Chow T, Black SE, Masellis M. Characterizing familial corticobasal syndrome due to Alzheimer's disease pathology and PSEN1 mutations. Alzheimers Dement. 2016 Oct 12; PubMed.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 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.
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.

Mutations

PSEN1 G378V

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