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NM_000484.4(APP):c.2017G>A (p.Ala673Thr) AND Alzheimer disease, protection against

Germline classification:
protective (1 submission)
Last evaluated:
Aug 2, 2012
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000030774.2

Allele description [Variation Report for NM_000484.4(APP):c.2017G>A (p.Ala673Thr)]

NM_000484.4(APP):c.2017G>A (p.Ala673Thr)

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.2017G>A (p.Ala673Thr)
Other names:
APP, ALA673THR (rs63750847)
HGVS:
  • NC_000021.9:g.25897620C>T
  • NG_007376.2:g.278509G>A
  • NM_000484.4:c.2017G>AMANE SELECT
  • NM_001136016.3:c.1945G>A
  • NM_001136129.3:c.1624G>A
  • NM_001136130.3:c.1849G>A
  • NM_001136131.3:c.1687G>A
  • NM_001204301.2:c.1963G>A
  • NM_001204302.2:c.1906G>A
  • NM_001204303.2:c.1738G>A
  • NM_001385253.1:c.1849G>A
  • NM_201413.3:c.1960G>A
  • NM_201414.3:c.1792G>A
  • NP_000475.1:p.Ala673Thr
  • NP_001129488.1:p.Ala649Thr
  • NP_001129601.1:p.Ala542Thr
  • NP_001129602.1:p.Ala617Thr
  • NP_001129603.1:p.Ala563Thr
  • NP_001191230.1:p.Ala655Thr
  • NP_001191231.1:p.Ala636Thr
  • NP_001191232.1:p.Ala580Thr
  • NP_001372182.1:p.Ala617Thr
  • NP_958816.1:p.Ala654Thr
  • NP_958817.1:p.Ala598Thr
  • NC_000021.8:g.27269932C>T
  • NG_007376.1:g.278201G>A
Protein change:
A542T; ALA673THR
Links:
OMIM: 104760.0023; dbSNP: rs63750847
NCBI 1000 Genomes Browser:
rs63750847
Molecular consequence:
  • NM_000484.4:c.2017G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136016.3:c.1945G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136129.3:c.1624G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136130.3:c.1849G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136131.3:c.1687G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204301.2:c.1963G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204302.2:c.1906G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204303.2:c.1738G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001385253.1:c.1849G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_201413.3:c.1960G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_201414.3:c.1792G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Alzheimer disease, protection against
Identifiers:
MedGen: C3549448

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000053435OMIM
no assertion criteria provided
protective
(Aug 2, 2012) 		germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.

Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, et al.

Nature. 2012 Aug 2;488(7409):96-9. doi: 10.1038/nature11283.

PubMed [citation]
PMID:
22801501

Details of each submission

From OMIM, SCV000053435.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Using whole-genome sequence data from 1,795 Icelanders, Jonsson et al. (2012) identified a coding SNP in the APP gene, rs63750847 (A673T). This SNP was significantly more common in a control group of individuals aged 85 years or older without a diagnosis of Alzheimer disease (104300) than in a group of Alzheimer disease patients (0.62% vs 0.13%, respectively; OR = 5.29; p = 4.78 x 10(-7)). The SNP was enriched among a group of controls who were cognitively intact at age 85 years (0.79%; OR = 7.52; p = 6.92 x 10(-6)). Among 3,673 noncarriers and 41 carriers of the A673T variant, all without a diagnosis of Alzheimer disease, Jonsson et al. (2012) found on average a 1.03-unit difference across the 80 to 100 age range on a test of cognitive performance (average 6.49 and 6.39 determinations per individual, respectively), with the carriers having a score indicative of better conserved cognition. By Western blot analysis of cell supernatants, Jonsson et al. (2012) found that the A673T variant results in reduced production of extracellular APP fragments generated by processing at the beta site with a slight increase in fragments produced using the alpha site. This observation was confirmed by immunoassay. Jonsson et al. (2012) also found that the production of amyloidogenic peptides A-beta-40 and A-beta-42 was approximately 40% less by the A673T variant than by wildtype APP. In contrast to A673T, the A673V substitution (104760.0022) resulted in markedly increased APP processing at the beta site, decreased processing at the alpha site, and greatly enhanced A-beta-40 and A-beta-42 production. These results were consistent with a protective effect of the A673T variant and illustrated clearly that position 673 of APP is capable of regulating proteolytic processing by BACE1 (604252).

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

Last Updated: Sep 29, 2024