ClinVar Miner

Submissions for variant NM_000484.4(APP):c.2149G>A (p.Val717Ile) (rs63750264)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000020308 SCV000935808 pathogenic Alzheimer's disease 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 717 of the APP protein (p.Val717Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with early-onset Alzheimer's disease (EOAD) in several families (PMID: 27838006, 25138979, 24650794). ClinVar contains an entry for this variant (Variation ID: 18088). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Experimental studies have shown that this missense change leads to increased amyloid beta levels and altered gamma- and beta-secretase cleavage of APP (PMID: 24524897, 19281847). In addition, a transgenic mouse model carrying this variant shows cognitive deficits and increased amyloid plaque formation (PMID: 11978821). This variant disrupts the p.Val717 amino acid residue in APP. Other variants that disrupt this residue have been observed in affected individuals (PMID: 1925564, 15776278), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000019714 SCV000040012 pathogenic Alzheimer disease, type 1 1996-10-23 no assertion criteria provided literature only
GeneReviews RCV000020308 SCV000040683 pathologic Alzheimer's disease 2010-12-23 no assertion criteria provided curation Converted during submission to Pathogenic.
VIB Department of Molecular Genetics, University of Antwerp RCV000084575 SCV000116711 not provided not provided no assertion provided not provided

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