ClinVar Miner

Submissions for variant NM_000447.3(PSEN2):c.422A>T (p.Asn141Ile) (rs63750215)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000009393 SCV000762646 pathogenic Alzheimer disease, type 4 2018-05-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 141 of the PSEN2 protein (p.Asn141Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with early onset Alzheimer's disease in several affected families (PMID: 26166204, 7638622). It has also been reported in many affected individuals of Volga German descent and represents a founder mutation in this population (PMID: 7651536, 19073399, 20457965, 16533963, 18833506, 24928124). ClinVar contains an entry for this variant (Variation ID: 8845). Experimental studies have shown that this missense change impacts several cellular processes associated with Alzheimer's disease, including amyloid-beta peptide metabolism, cellular calcium homeostasis and apoptosis (PMID: 16959576, 22115042, 8986743, 15663477, 20634584, 9050898, 22249458). In addition, transgenic mice carrying this missense variant recapitulate aspects of the Alzheimer's disease phenotype (PMID: 21234330). 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).
OMIM RCV000009393 SCV000029611 pathogenic Alzheimer disease, type 4 2011-09-01 no assertion criteria provided literature only
GeneReviews RCV000009393 SCV000040676 pathologic Alzheimer disease, type 4 2010-12-23 no assertion criteria provided curation Converted during submission to Pathogenic.
VIB Department of Molecular Genetics, University of Antwerp RCV000084262 SCV000116398 not provided not provided no assertion provided not provided

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