NM_000484.4(APP):c.2010_2011inv (p.Lys670_Met671delinsAsnLeu) AND Alzheimer disease

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 5, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000034924.11

Allele description [Variation Report for NM_000484.4(APP):c.2010_2011inv (p.Lys670_Met671delinsAsnLeu)]

NM_000484.4(APP):c.2010_2011inv (p.Lys670_Met671delinsAsnLeu)

Gene:

APP:amyloid beta precursor protein [Gene - OMIM - HGNC]

Variant type:

Inversion

Cytogenetic location:

21q21.3

Genomic location:

Preferred name:

NM_000484.4(APP):c.2010_2011inv (p.Lys670_Met671delinsAsnLeu)

HGVS:

NC_000021.9:g.25897626_25897627inv
NG_007376.2:g.278502_278503inv
NM_000484.4:c.2010_2011invMANE SELECT
NM_001136016.3:c.1938_1939inv
NM_001136129.3:c.1617_1618inv
NM_001136130.3:c.1842_1843inv
NM_001136131.3:c.1680_1681inv
NM_001204301.2:c.1956_1957inv
NM_001204302.2:c.1899_1900inv
NM_001204303.2:c.1731_1732inv
NM_001385253.1:c.1842_1843inv
NM_201413.3:c.1953_1954inv
NM_201414.3:c.1785_1786inv
NP_000475.1:p.Lys670_Met671delinsAsnLeu
NP_001129488.1:p.Lys646_Met647delinsAsnLeu
NP_001129601.1:p.Lys539_Met540delinsAsnLeu
NP_001129602.1:p.Lys614_Met615delinsAsnLeu
NP_001129603.1:p.Lys560_Met561delinsAsnLeu
NP_001191230.1:p.Lys652_Met653delinsAsnLeu
NP_001191231.1:p.Lys633_Met634delinsAsnLeu
NP_001191232.1:p.Lys577_Met578delinsAsnLeu
NP_001372182.1:p.Lys614_Met615delinsAsnLeu
NP_958816.1:p.Lys651_Met652delinsAsnLeu
NP_958817.1:p.Lys595_Met596delinsAsnLeu
NC_000021.8:g.27269938_27269939delinsGA
NC_000021.8:g.27269938_27269939inv
NG_007376.1:g.278194_278195delinsTC
NM_000484.2:c.2010_2011delinsTC
NM_000484.3:c.2010_2011delinsTC
NM_000484.3:c.2010_2011inv
NM_000484.4:c.2010_2011delinsTCMANE SELECT

Protein change:

LYS670ASN AND MET671LEU

Links:

OMIM: 104760.0008; dbSNP: rs281865161

NCBI 1000 Genomes Browser:

rs281865161

Molecular consequence:

NM_000484.4:c.2010_2011inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001136016.3:c.1938_1939inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001136129.3:c.1617_1618inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001136130.3:c.1842_1843inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001136131.3:c.1680_1681inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001204301.2:c.1956_1957inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001204302.2:c.1899_1900inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001204303.2:c.1731_1732inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001385253.1:c.1842_1843inv - missense variant - [Sequence Ontology: SO:0001583]
NM_201413.3:c.1953_1954inv - missense variant - [Sequence Ontology: SO:0001583]
NM_201414.3:c.1785_1786inv - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000058531	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (8) [See all records that cite these PMIDs] 1302033, 1465129, 7489411, 8012386, 8810256, 9371838, 9796810, 20301414
SCV000951935	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 24, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8810256, 21335619, 23649480, 28492532
SCV004804178	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8012386, 36626935, 1302033, 21335619, 9371838, 28209190 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000058531

GeneReviews

no classification provided

not provided

unknown

literature only

PubMed (8)
[See all records that cite these PMIDs]

SCV000951935

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 24, 2018)

germline

clinical testing

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

SCV004804178

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 5, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production.

Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ.

Nature. 1992 Dec 17;360(6405):672-4.

PubMed [citation]

PMID:: 1465129

The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway.

Haass C, Lemere CA, Capell A, Citron M, Seubert P, Schenk D, Lannfelt L, Selkoe DJ.

Nat Med. 1995 Dec;1(12):1291-6.

PubMed [citation]

PMID:: 7489411

See all PubMed Citations (13)

Details of each submission

From GeneReviews, SCV000058531.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000951935.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this sequence change disrupts protein function in vivo and in vitro (PMID: 8810256, 21335619, 23649480). This variant, commonly known as the "Swedish mutation", has been observed to segregate with¬†Alzheimer‚Äôs disease¬†in several families (PMID:¬†1302033). ClinVar contains an entry for this variant (Variation ID: 18093). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine and methionine with asparagine and leucine at codons 670-671 of the APP protein (p.Lys670_Met671delinsAsnLeu).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004804178.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: APP c.2010_2011delinsTC (p.Lys670_Met671delinsAsnLeu) results in an in-frame deletion-insertion that is predicted to replace 2 amino acids in the protein. The variant was absent in 251394 control chromosomes (gnomAD). The variant, c.2010_2011delinsTC (aka. APPswe, KM670/671NL), is a well-known variant that has been reported in the literature in Swedish families with multiple family members affected with Alzheimer Disease (e.g. Mullan_1992, Shafaati_2011, Thordardottir_2017, Johansson_2023). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant causes ~5-10-fold increase in the production of the amyloidogenic C-terminal peptide fragments (e.g. Felsenstein_1992), and results in pathological features reminiscent of Alzheimer Disease pathology in transgenic mice (e.g. Sturchler-Pierrat_1997). The following publications have been ascertained in the context of this evaluation (PMID: 1302033, 21335619, 28209190 , 36626935, 8012386, 9371838). ClinVar contains an entry for this variant (Variation ID: 18093). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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