Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226888975 T>C
Position: (GRCh37/hg19):Chr1:227076676 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTC to CCC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8

Findings

This variant was identified in a German individual of European descent who developed progressive aphasia at age 54, along with memory problems (Blauwendraat et al., 2015). Speech was slow and verbal expression difficult. Behavioral symptoms developed later. The patient died at age 60. Family history was negative for neurological disease.

In addition, L238P was identified in two individuals with late-onset AD from a case-control cohort of the Alzheimer’s Disease Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 5,844 cases and 4,767 controls, most of European-American ancestry (Fernández et al., 2017). Ages at onset were 63 and 80 years. Also, as reported in a preprint analyzing a newer release from the ADSP, including data from 13,825 AD cases and 14,715 controls, L238P was identified in four individuals with AD (Wang et al., 2023, suppl table e-5). In both studies, the variant was absent from controls.

Koriath and colleagues described L238P as likely having reduced penetrance, with an allele count of three, and a frequency of 0.0012 percent in the gnomAD variant database (Koriath et al., 2018). All three reported carriers in gnomAD were non-Finnish Europeans.

Neuropathology

Neuropathological data are unavailable. MRI showed supratentorial cortical atrophy, particularly atrophy of the parietal cortex in the German patient (Blauwendraat et al., 2015).

Biological Effect

The biological effect of this variant is unknown, however, in silico, this mutation is predicted to be damaging (PHRED-scaled CADD score = 26.7; CADD v.1.6, Nov 2021; damaging metaSVM score from dbNFSP v. 4.3a, Wang et al., 2023).

Pathogenicity

Alzheimer's Disease : Uncertain Significance*

*This variant may have reduced penetrance, a condition outside the scope of the ACMG-AMP guidelines.

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

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References

Paper Citations

1. Blauwendraat C, Wilke C, Jansen IE, Schulte C, Simón-Sánchez J, Metzger FG, Bender B, Gasser T, Maetzler W, Rizzu P, Heutink P, Synofzik M. Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiol Aging. 2016 Jan;37:208.e11-7. Epub 2015 Sep 30 PubMed.
2. Fernández MV, Kim JH, Budde JP, Black K, Medvedeva A, Saef B, Deming Y, Del-Aguila J, Ibañez L, Dube U, Harari O, Norton J, Chasse R, Morris JC, Goate A, NIA-LOAD family study group, NCRAD, Cruchaga C. Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease. PLoS Genet. 2017 Nov;13(11):e1007045. PubMed.
3. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, The Alzheimer's Disease Sequencing Project, DeStefano AL, Peloso GM. Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.
4. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.

Further Reading

No Available Further Reading