rs281865161

chr21-25897626-TC-GA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_000484.4(APP):c.2010_2011inv(p.Lys670_Met671delinsAsnLeu) variant causes a missense change. 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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, 6 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 id is 18093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APP	NM_000484.4	c.2010_2011inv	p.Lys670_Met671delinsAsnLeu	missense_variant	16/18	ENST00000346798.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APP	ENST00000346798.8	c.2010_2011inv	p.Lys670_Met671delinsAsnLeu	missense_variant	16/18	1	NM_000484.4

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 24, 2018	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). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 05, 2024	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. -

APP-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2023

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 22, 1998

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not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs281865161; hg19: chr21-27269938;