rs281865161

Variant names:

• chr21-25897626-TC-GA
• rs281865161
• NM_000484.4:c.2010_2011delGAinsTC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_000484.4(APP):​c.2010_2011delGAinsTC​(p.LysMet670AsnLeu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K670K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APP NM_000484.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 6.73
• Publications: 3 publications found

Genes affected

APP (HGNC:620): (amyloid beta precursor protein) This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. In addition, two of the peptides are antimicrobial peptides, having been shown to have bacteriocidal and antifungal activities. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2014]

APP Gene-Disease associations (from GenCC):

• Alzheimer disease type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• cerebral amyloid angiopathy, APP-related

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ABeta amyloidosis, Arctic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, dutch type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, Iowa type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABeta amyloidosis, Italian type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABetaA21G amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ABetaL34V amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000484.4
• PP5: Variant 21-25897626-TC-GA is Pathogenic according to our data. Variant chr21-25897626-TC-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 18093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.2010_2011delGAinsTC	p.LysMet670AsnLeu	missense_variant		ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.2010_2011delGAinsTC	p.LysMet670AsnLeu	missense_variant		1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alzheimer disease Pathogenic:2 Other:1

Jan 05, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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’s 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).

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

APP-related disorder Pathogenic:1

May 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APP c.2010_2011delinsTC variant is predicted to result in an in-frame deletion and insertion. This variant has been reported in multiple individuals with Alzheimer's disease (Mullan et al. 1992. PubMed ID: 1302033). Several transgenic mouse models demonstrate this variant, often referred to as the Swedish mutant, having a negative effect on APP function (Aso et al. 2012. PubMed ID: 22188425; Cuddy et al. 2015. PubMed ID: 25970623; Felsenstein et al. 1994. PubMed ID: 8012386; Sturchler-Pierrat C et al. 1997. PubMed ID: 9371838; Katsurabayashi et al. 2016. PubMed ID: 26733247; Munter et al. 2010. PubMed ID: 20452985; Rabe et al. 2011. PubMed ID: 21812781; Rodrigues et al. 2012. PubMed ID: 22843498). Additionally, autopsies of Alzheimer’s patients carrying this variant revealed a 4-fold accumulation of 27-hydroxycholesterol levels across different cortexes of the brain (Shafaati et al. 2011. PubMed ID: 21335619). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted to be pathogenic.

Alzheimer disease type 1 Pathogenic:1

Oct 22, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Other:1

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=0/200	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs281865161; hg19: chr21-27269938;