Submissions for variant NM_000447.3(PSEN2):c.422A>T (p.Asn141Ile)

dbSNP: rs63750215

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000009393	SCV000762646	pathogenic	Alzheimer disease 4	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 141 of the PSEN2 protein (p.Asn141Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset Alzheimer's disease (PMID: 7638622, 7651536, 16533963, 18833506, 19073399, 20457965, 24928124, 26166204). It is commonly reported in individuals of German ancestry (PMID: 7651536, 16533963, 18833506, 19073399, 20457965, 24928124). ClinVar contains an entry for this variant (Variation ID: 8845). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSEN2 protein function. Experimental studies have shown that this missense change affects PSEN2 function (PMID: 8986743, 9050898, 15663477, 16959576, 20634584, 21234330, 22115042, 22249458). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000084262	SCV001145229	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/282490 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Statistically associated with disease in multiple families (p<0.0001).
CeGaT Center for Human Genetics Tuebingen	RCV000084262	SCV001250073	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000084262	SCV002513134	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate N141I resulted in impaired secretase activity as well as exaggerated inflammatory cytokine release, NFKB activity, and A-beta internalization (Fung et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20457965, 7651536, 33084218, 30412492, 31020001, 25323700, 24594196, 24093083, 20301414, 22805202, 21911706, 22505025, 21559247, 20333730, 7638622, 16533963, 15776278, 16155344, 15663477, 15389756, 9813158, 10846187, 8939861, 7550356, 9050898, 8986743, 22115042, 23365231, 16959576, 20634584, 21234330, 22249458, 30954774, 26166204, 9450781, 24928124, 8661049, 19073399, 18833506, 20375137, 30822648, 32087291, 32032730, 32741831)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000009393	SCV002559862	pathogenic	Alzheimer disease 4	2022-08-12	criteria provided, single submitter	clinical testing
OMIM	RCV000009393	SCV000029611	pathogenic	Alzheimer disease 4	2011-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000009393	SCV000040676	not provided	Alzheimer disease 4		no assertion provided	literature only
VIB Department of Molecular Genetics, University of Antwerp	RCV000084262	SCV000116398	not provided	not provided		no assertion provided	not provided