NM_000484.3(APP):c.2010_2011delGAinsTC (p.Lys670_Met671delinsAsnLeu)

NM_000484.3(APP):c.2010_2011delGAinsTC (p.Lys670_Met671delinsAsnLeu)

Variant type:
Cytogenetic location:
Genomic location:
  • Chr21:25897626 - 25897627 (on Assembly GRCh38)
  • Chr21:27269938 - 27269939 (on Assembly GRCh37)
Protein change:
K670N, M671L
  • NG_007376.1:g.278194_278195delGAinsTC
  • NM_000484.3:c.2010_2011delGAinsTC
  • NC_000021.9:g.25897626_25897627delTCinsGA (GRCh38)
  • NC_000021.8:g.27269938_27269939delTCinsGA (GRCh37)
  • NG_007376.1:g.278194_278195delinsTC
  • NP_000475.1:p.Lys670_Met671delinsAsnLeu
  • NM_000484.2:c.2010_2011delinsTC
  • NM_000484.3:c.2010_2011delinsTC
  • NM_000484.2:c.2010_2011delGAinsTC
NCBI 1000 Genomes Browser:
Molecular consequence:
NM_000484.3:c.2010_2011delGAinsTC: missense variant [Sequence Ontology SO:0001583]

Clinical significance

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Assertion and evidence details


Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
(Last submitted)
Submission accession
(Sep 4, 2013)
classified by single submitter
(literature only)
literature only
  • Alzheimer disease, type 1[MedGen]
germlinePubMed (8)
(Dec 30, 2010)
(Dec 23, 2010)
classified by single submitter
(literature only)
literature onlynot providedPubMed (8)
(Mar 26, 2013)
not providednot classified by submitter
(literature only)
literature onlynot providedVIB Department of Molecular Genetics, University of Antwerp
(Feb 13, 2013)


FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermline, not providednot providednot provided


Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providednot provided

Neurodegenerative Brain Diseases Group

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providednot provided


Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline


Calhoun et al. (1998) studied the pattern of neuron loss in transgenic mice expressing mutant human APP with the 'Swedish mutation.' These mice develop APP-immunoreactive plaques, primarily in neocortex and hippocampus, progressively with age (Sturchler-Pierrat et al., 1997). Calhoun et al. (1998) showed that formation of amyloid plaques led to region-specific loss of neurons in the transgenic mouse. Neuron loss was observed primarily in the vicinity of plaques, but intraneuronal amyloidogenic APP processing could not be excluded as an additional cause. The extent of the observed loss was less than that reported in end-stage AD, possibly because overexpression of APP in the transgenic mouse had a neuroprotective effect.
Citron et al. (1994) found that fibroblasts isolated from the Swedish family with the double APP mutation, continuously secreted a homogeneous population of beta-amyloid molecules starting at asp-1 (D672 of beta-APP). There was a consistent and significant elevation of approximately 3-fold of beta-amyloid release from all biopsied skin fibroblasts bearing the FAD mutation. The elevated beta-amyloid levels were found in cells from both patients with clinical Alzheimer disease and presymptomatic subjects, indicating that it is not a secondary event and may play a causal role in the development of the disease. Haass et al. (1995) showed that the increased production of amyloid beta peptide associated with the 'Swedish mutation' resulted from a cellular mechanism which differs substantially from that responsible for the production of amyloid beta peptide from the wildtype gene. In the latter case, A-beta generation requires reinternalization and recycling of the precursor protein. In the Swedish mutation, the N-terminal beta-secretase cleavage of A-beta occurred in Golgi-derived vesicles, most likely within secretory vesicles. Therefore, this cleavage occurred in the same compartment as the alpha-secretase cleavage, which normally prevents A-beta production, explaining the increased A-beta generation by a competition between alpha- and beta-secretase.
Felsenstein et al. (1994) found that a neuroglioma cell line expressing the Swedish FAD double mutation showed a consistent 5- to 7-fold increase in the level of the 11-kD potentially amyloidogenic C-terminal fragment. The increase appeared to result from altered cleavage specificity in the secretory pathway from the nonamyloidogenic alpha-secretase site at lys16 to an alternative site at or near the N terminus of the beta protein.
Hsiao et al. (1996) found that transgenic mice overexpressing the Swedish double mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age, but showed impairment by 9 to 10 months of age. Brains of the older mice showed a 5-fold increase in the concentration of beta-amyloid derivatives and classic senile plaques with dense amyloid cores.
In affected members of 2 large Swedish families with early-onset familial Alzheimer disease (104300), Mullan et al. (1992) identified a double mutation in exon 16 of the APP gene: a G-to-T transversion, resulting in lys670-to-asn (K670N) substitution, and an A-to-C transversion, resulting in a met671-to-leu (M671L) substitution. Mullan et al. (1992) suggested that this mutation, which occurs at the amino terminal of beta-amyloid, may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. The mean age at onset was 55 years. The 2 families were found to be linked by genealogy. Citron et al. (1992) reported that cultured cells that express an APP cDNA bearing this double mutation produced 6 to 8 times more amyloid beta-protein than cells expressing the normal APP gene. They showed that the met596-to-leu mutation was principally responsible for the increase. (MET596LEU in the APP695 transcript is the equivalent of MET671LEU in the APP770 transcript, which was the basis of the numbering system used by Mullan et al. (1992).) These findings established a direct link between genotype and phenotype.
Sturchler-Pierrat et al. (1997) observed pathologic features reminiscent of AD in 2 lines of transgenic mice expressing human APP mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670 to 671 combined with the V717I mutation (104760.0002) caused amyloid beta deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits were mostly of the diffuse type; however, some congophilic plaques could be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appeared at 6 months, which increased with age and were Congo Red-positive at first detection. These congophilic plaques were accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction were apparent. Most notably, the plaques were immunoreactive for hyperphosphorylated tau (MAPT; 157140), reminiscent of early tau pathology. These findings supported a central role of beta-amyloid in the pathogenesis of AD.

Last Updated: Jan 28, 2015

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