ClinVar Miner

Submissions for variant NM_000021.4(PSEN1):c.737C>A (p.Ala246Glu) (rs63750526)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542870 SCV000639608 pathogenic Alzheimer disease, type 3; Frontotemporal dementia; Pick's disease; Acne inversa, familial, 3 2017-09-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 246 of the PSEN1 protein (p.Ala246Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with early onset Alzheimer’s disease (AD) in a single family (PMID: 7596406) and in individuals affected with early onset AD (PMID: 25174650, Invitae). ClinVar contains an entry for this variant (Variation ID: 18125). Experimental studies have shown that this missense change in human skin fibroblasts exhibits elevated lysosomal pH, reduced availability of active cathepsin D, reduces cleavage to the mature form of the enzyme, and also impairs degradation of autophagic substrates as compared to levels from control fibroblasts (PMID: 24418614). This variant also decreases rescuing activity in C. elegans (PMID: 9680315) and mice expressing the human A246E transgene show increased amyloid beta in the absence of plaques (PMID: 12493631). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000019753 SCV000040051 pathogenic Alzheimer disease, type 3 1995-06-29 no assertion criteria provided literature only
VIB Department of Molecular Genetics, University of Antwerp RCV000084361 SCV000116497 not provided not provided no assertion provided not provided

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