21-25897642-C-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_000484.4(APP):c.1995G>C(p.Glu665Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000484.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APP | NM_000484.4 | c.1995G>C | p.Glu665Asp | missense_variant | Exon 16 of 18 | ENST00000346798.8 | NP_000475.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251368Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135856
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461612Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 20AN XY: 727114
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74348
ClinVar
Submissions by phenotype
not provided Uncertain:1Other:1
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, -
- -
Alzheimer disease type 1 Pathogenic:1
- -
APP-related disorder Uncertain:1
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. -
Alzheimer disease Uncertain:1
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). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at