rs281865161

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000951935: Experimental studies have shown that this sequence change disrupts protein function in vivo and in vitro (PMID:8810256, 21335619, 23649480)." and additional evidence is available in ClinVar. 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):

• cerebral amyloid angiopathy, APP-related

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• Alzheimer disease type 1

  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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000951935: Experimental studies have shown that this sequence change disrupts protein function in vivo and in vitro (PMID: 8810256, 21335619, 23649480).; SCV004804178: 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). PMID: 1302033, 21335619, 28209190 , 36626935, 8012386, 9371838; SCV004112130: 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).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	NM_000484.4	MANE Select	c.2010_2011delGAinsTC	p.LysMet670AsnLeu	missense	N/A	NP_000475.1	P05067-1
	APP	NM_001204301.2		c.1956_1957delGAinsTC	p.LysMet652AsnLeu	missense	N/A	NP_001191230.1	P05067-9
	APP	NM_201413.3		c.1953_1954delGAinsTC	p.LysMet651AsnLeu	missense	N/A	NP_958816.1	P05067-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APP	ENST00000346798.8	TSL:1 MANE Select	c.2010_2011delGAinsTC	p.LysMet670AsnLeu	missense	N/A	ENSP00000284981.4	P05067-1
	APP	ENST00000357903.7	TSL:1	c.1953_1954delGAinsTC	p.LysMet651AsnLeu	missense	N/A	ENSP00000350578.3	P05067-8
	APP	ENST00000439274.6	TSL:1	c.1842_1843delGAinsTC	p.LysMet614AsnLeu	missense	N/A	ENSP00000398879.2	E9PG40

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Alzheimer disease (3)
1	-	-	Alzheimer disease type 1 (1)
1	-	-	APP-related disorder (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs281865161;

hg19: chr21-27269938;