Overview

Pathogenicity: Alzheimer's Disease : Likely Benign
ACMG/AMP Pathogenicity Criteria: PP2, BS1, BP4
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73678599 G>A
dbSNP ID: rs199715992
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to ACT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 10

Findings

This variant was identified in a French study that screened 129 individuals with sporadic AD diagnosed according to the National Institute of Aging–Alzheimer’s Association criteria with an age at onset below 51 (Lanoiselée et al., 2017, Lacour et al., 2019). The mutation carrier had progressive cognitive decline beginning at age 45, and a disease duration of seven years. The carrier was homozygous for the APOE3 allele. It is unknown if the mutation arose de novo, as parental DNA was unavailable.

Two additional carriers from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were identified in a subsequent study (Küçükali et al., 2022). One was cognitively healthy at age 68, but developed dementia by age 72. The other was diagnosed with mild cognitive impairment (MCI) at age 70, and received the same diagnosis at age 75 without having progressed to demenia.

The variant was found in the gnomAD variant database at a frequency of 0.00003183 with an allele count of nine (gnomAD v2.1.1, Sep 2021). In a subset of the gnomAD database that excludes data from neurological studies, the frequency was similar, 0.00003925, with the same allele count (gnomAD v2.1.1 (non-neuro), Sep 2021).

Neuropathology
Neuropathological data are unavailable. Cerebrospinal fluid biomarkers for AD were measured in two mutation carriers. In the carrier diagnosed with AD, levels of Aβ42 were reduced consistent with AD, but tau and phospho-tau were in the normal range (Lanoiselée et al., 2017). In contrast, the carrier diagnosed with stable MCI had normal levels of both Aβ42 and tau, but elevated levels of phospo-tau181 (Küçükali et al., 2022). The AD patient had posterior cortical atrophy and hippocampal atrophy with mild non-specific leukopathy as revealed by an MRI scan (Lacour et al., 2019).

Biological Effect
The biological effect of this mutation is unknown. In silico algorithms to predict its effects (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021) and the CADD-PHRED tool, which integrates diverse information, gave it a score of 19.2, just below the commonly used deleteriousness threshold of 20 (CADD v.1.6, Sep 2021). Based on the criteria developed by Guerreiro and colleagues (Guerreiro et al., 2010), this mutation was classified as possibly pathogenic (Lanoiselée et al., 2017) and of uncertain significance based on the ACMG/AMP guidelines (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely Benign

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database. A360T: Most carriers were of European ancestry.

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: 23 Jan 2023

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References

Paper Citations

Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
Lacour M, Quenez O, Rovelet-Lecrux A, Salomon B, Rousseau S, Richard AC, Quillard-Muraine M, Pasquier F, Rollin-Sillaire A, Martinaud O, Zarea A, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Magnin E, Sauvée M, Marelli C, Gabelle A, Pariente J, Paquet C, Boland A, Deleuze JF, Campion D, Hannequin D, Nicolas G, Wallon D, collaborators of the CNR-MAJ. Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer's Disease Before 51 Years. J Alzheimers Dis. 2019;71(1):227-243. PubMed.
Küçükali F, Neumann A, Van Dongen J, De Pooter T, Joris G, De Rijk P, Ohlei O, Dobricic V, Bos I, Vos SJ, Engelborghs S, De Roeck E, Vandenberghe R, Gabel S, Meersmans K, Tsolaki M, Verhey F, Martinez-Lage P, Tainta M, Frisoni G, Blin O, Richardson JC, Bordet R, Alzheimer's Disease Neuroimaging Initiative (ADNI), Scheltens P, Popp J, Peyratout G, Johannsen P, Frölich L, Freund-Levi Y, Streffer J, Lovestone S, Legido-Quigley C, Kate MT, Barkhof F, Zetterberg H, Bertram L, Strazisar M, Visser PJ, Van Broeckhoven C, Sleegers K, EMIF-AD Study Group. Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits. Alzheimers Dement. 2022 Dec 4; 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.
Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 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

PSEN1 A360T

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