Submissions for variant NM_000484.4(APP):c.1726G>A (p.Val576Ile)

gnomAD frequency: 0.00006  dbSNP: rs200769792

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001038003	SCV001201444	uncertain significance	Alzheimer disease	2022-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 576 of the APP protein (p.Val576Ile). This variant is present in population databases (rs200769792, gnomAD 0.01%). This missense change has been observed in individual(s) with early-onset Alzheimer disease and/or small vessel ischemic disease (PMID: 32345996; Invitae). ClinVar contains an entry for this variant (Variation ID: 836798). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689964	SCV005184948	uncertain significance	not specified	2024-05-30	criteria provided, single submitter	clinical testing	Variant summary: APP c.1726G>A (p.Val576Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251456 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in APP causing Cerebral Amyloid Angiopathy, APP-Related, allowing no conclusion about variant significance. c.1726G>A has been reported in the literature in two individuals affected with early-onset small vessel ischemic disease and Alzheimers Disease (Blumenau_2020, Rehker_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cerebral Amyloid Angiopathy, APP-Related. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32345996, 28985224). ClinVar contains an entry for this variant (Variation ID: 836798). Based on the evidence outlined above, the variant was classified as uncertain significance.