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NM_000484.4(APP):c.2125G>A (p.Gly709Ser) AND Alzheimer disease

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Nov 6, 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:
RCV001869244.5

Allele description [Variation Report for NM_000484.4(APP):c.2125G>A (p.Gly709Ser)]

NM_000484.4(APP):c.2125G>A (p.Gly709Ser)

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.2125G>A (p.Gly709Ser)
HGVS:
  • NC_000021.9:g.25891808C>T
  • NG_007376.2:g.284321G>A
  • NM_000484.4:c.2125G>AMANE SELECT
  • NM_001136016.3:c.2053G>A
  • NM_001136129.3:c.1732G>A
  • NM_001136130.3:c.1957G>A
  • NM_001136131.3:c.1795G>A
  • NM_001204301.2:c.2071G>A
  • NM_001204302.2:c.2014G>A
  • NM_001204303.2:c.1846G>A
  • NM_001385253.1:c.1957G>A
  • NM_201413.3:c.2068G>A
  • NM_201414.3:c.1900G>A
  • NP_000475.1:p.Gly709Ser
  • NP_001129488.1:p.Gly685Ser
  • NP_001129601.1:p.Gly578Ser
  • NP_001129602.1:p.Gly653Ser
  • NP_001129603.1:p.Gly599Ser
  • NP_001191230.1:p.Gly691Ser
  • NP_001191231.1:p.Gly672Ser
  • NP_001191232.1:p.Gly616Ser
  • NP_001372182.1:p.Gly653Ser
  • NP_958816.1:p.Gly690Ser
  • NP_958817.1:p.Gly634Ser
  • NC_000021.8:g.27264120C>T
Protein change:
G578S
Links:
dbSNP: rs201269325
NCBI 1000 Genomes Browser:
rs201269325
Molecular consequence:
  • NM_000484.4:c.2125G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136016.3:c.2053G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136129.3:c.1732G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136130.3:c.1957G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136131.3:c.1795G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204301.2:c.2071G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204302.2:c.2014G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204303.2:c.1846G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001385253.1:c.1957G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_201413.3:c.2068G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_201414.3:c.1900G>A - 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
SCV002223862Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Nov 6, 2023) 		germlineclinical testing

PubMed (2)
[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

Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease.

Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, Kurz A, Diehl-Schmid J, Hüll M, Lichtner P, Eckstein G, Zimprich A, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Lorenzo-Betancor O, Pastor P, Peters A, Gieger C, Estivill X, et al.

Eur J Hum Genet. 2015 Oct;23(10):1328-33. doi: 10.1038/ejhg.2014.300. Epub 2015 Jan 21.

PubMed [citation]
PMID:
25604855
PMCID:
PMC4592093

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV002223862.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 709 of the APP protein (p.Gly709Ser). This variant is present in population databases (rs201269325, gnomAD 0.02%). This missense change has been observed in individual(s) with Parkinson disease and dementia (PMID: 25604855). ClinVar contains an entry for this variant (Variation ID: 638317). 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 expected to disrupt APP protein function with a positive predictive value of 95%. 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