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NM_000484.4(APP):c.1995G>C (p.Glu665Asp) AND Alzheimer disease

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
May 22, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003509482.1

Allele description [Variation Report for NM_000484.4(APP):c.1995G>C (p.Glu665Asp)]

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

Gene:
APP:amyloid beta precursor protein [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
21q21.3
Genomic location:
Preferred name:
NM_000484.4(APP):c.1995G>C (p.Glu665Asp)
HGVS:
  • NC_000021.9:g.25897642C>G
  • NG_007376.2:g.278487G>C
  • NM_000484.4:c.1995G>CMANE SELECT
  • NM_001136016.3:c.1923G>C
  • NM_001136129.3:c.1602G>C
  • NM_001136130.3:c.1827G>C
  • NM_001136131.3:c.1665G>C
  • NM_001204301.2:c.1941G>C
  • NM_001204302.2:c.1884G>C
  • NM_001204303.2:c.1716G>C
  • NM_001385253.1:c.1827G>C
  • NM_201413.3:c.1938G>C
  • NM_201414.3:c.1770G>C
  • NP_000475.1:p.Glu665Asp
  • NP_001129488.1:p.Glu641Asp
  • NP_001129601.1:p.Glu534Asp
  • NP_001129602.1:p.Glu609Asp
  • NP_001129603.1:p.Glu555Asp
  • NP_001191230.1:p.Glu647Asp
  • NP_001191231.1:p.Glu628Asp
  • NP_001191232.1:p.Glu572Asp
  • NP_001372182.1:p.Glu609Asp
  • NP_958816.1:p.Glu646Asp
  • NP_958817.1:p.Glu590Asp
  • NC_000021.8:g.27269954C>G
  • NG_007376.1:g.278179G>C
  • NM_000484.3:c.1995G>C
  • P05067:p.Glu665Asp
Protein change:
E534D; GLU665ASP
Links:
UniProtKB: P05067#VAR_010107; OMIM: 104760.0010; dbSNP: rs63750363
NCBI 1000 Genomes Browser:
rs63750363
Molecular consequence:
  • NM_000484.4:c.1995G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136016.3:c.1923G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136129.3:c.1602G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136130.3:c.1827G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136131.3:c.1665G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204301.2:c.1941G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204302.2:c.1884G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204303.2:c.1716G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001385253.1:c.1827G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_201413.3:c.1938G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_201414.3:c.1770G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Alzheimer disease
Synonyms:
Presenile and senile dementia; Alzheimer's disease
Identifiers:
MONDO: MONDO:0004975; MeSH: D000544; MedGen: C0002395; Orphanet: 1020; Human Phenotype Ontology: HP:0002511

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004281500Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(May 22, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Novel amyloid precursor protein gene mutation (codon 665Asp) in a patient with late-onset Alzheimer's disease.

Peacock ML, Murman DL, Sima AA, Warren JT Jr, Roses AD, Fink JK.

Ann Neurol. 1994 Apr;35(4):432-8.

PubMed [citation]
PMID:
8154870

Amyloid Precursor Protein Variant, E665D, Associated With Unique Clinical and Biomarker Phenotype.

Abbatemarco JR, Jones SE, Larvie M, Bekris LM, Khrestian ME, Krishnan K, Leverenz JB.

Am J Alzheimers Dis Other Demen. 2021 Jan-Dec;36:1533317520981225. doi: 10.1177/1533317520981225.

PubMed [citation]
PMID:
33445953
PMCID:
PMC10580711
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV004281500.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

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). Experimental studies have shown that this missense change does not substantially affect APP function (PMID: 32087291). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 20, 2024