Submissions for variant NM_000484.4(APP):c.1995G>C (p.Glu665Asp)

gnomAD frequency: 0.00001  dbSNP: rs63750363

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000084557	SCV000568676	uncertain significance	not provided	2017-03-14	criteria provided, single submitter	clinical testing	The E665D variant in the APP gene has been reported previously in the heterozygous state in a woman with late-onset Alzheimer disease; however further evidence supporting pathogenicity was not provided (Peacock et al., 1994). Additionally, this variant was not present in this individual's son with memory problems and other medical issues, but was observed in an asymptomatic relative who was over the age of 65 (Peacock et al., 1994). The E665D variant is observed in 1/66730 (0.0015%) alleles from individuals of European (Non-Finnish) background, in the ExAC dataset (Lek et al., 2016). The E665D variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E665D as a variant of uncertain significance,
Labcorp Genetics (formerly Invitae), Labcorp	RCV003509482	SCV004281500	uncertain significance	Alzheimer disease	2023-05-22	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change does not substantially affect APP function (PMID: 32087291). 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 not expected to disrupt APP protein function. ClinVar contains an entry for this variant (Variation ID: 18095). This missense change has been observed in individual(s) with clinical features of APP-related conditions (PMID: 8154870, 33445953). This variant is present in population databases (rs63750363, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 665 of the APP protein (p.Glu665Asp).
OMIM	RCV000019722	SCV000040020	pathogenic	Alzheimer disease type 1	1994-04-01	no assertion criteria provided	literature only
VIB Department of Molecular Genetics, University of Antwerp	RCV000084557	SCV000116693	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004745164	SCV005364052	uncertain significance	APP-related disorder	2024-05-31	no assertion criteria provided	clinical testing	The APP c.1995G>C variant is predicted to result in the amino acid substitution p.Glu665Asp. This variant was reported in an individual with late-onset Alzheimer's disease (AD) (Peacock et al. 1994. PubMed ID: 8154870). It was also reported in an individual with early-onset progressive cognitive and behavioral dysfunction and markers in the cerebrospinal fluid (CSF) consistent with Alzheimer's disease (Abbatemarco et al. 2021. PubMed ID: 33445953). In a functional study, it was reported not to increase levels of Aβ42/40 or Aβ42, and was considered not pathogenic (Hsu et al. 2020. PubMed ID: 32087291). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.