rs63750579

Positions:

• chr21-25891856-C-G
• chr21-25891856-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000346798.8(APP):​c.2077G>C​(p.Glu693Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E693G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APP ENST00000346798.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.73

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 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000346798.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-25891855-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 18098.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 21-25891856-C-G is Pathogenic according to our data. Variant chr21-25891856-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 18087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APP	NM_000484.4	c.2077G>C	p.Glu693Gln	missense_variant	17/18	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.2077G>C	p.Glu693Gln	missense_variant	17/18	1	NM_000484.4	ENSP00000284981

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ABeta amyloidosis, dutch type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

Cerebral amyloid angiopathy, APP-related Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Toxic gain of function is a known mechanism of disease in this gene and is associated with Alzheimer disease 1, familial (MIM#104300) (PMID: 24524897). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. p.(Ala713Thr) has been reported to exhibit reduced penetrance (PMID: 28350801). (I) 0115 - Variants in this gene are known to have variable expressivity. Age of onset and disease progression can vary (GeneReviews; PMID: 24650794). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0703 – Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. An alternative change to a lysine has been reported in one individual with hereditary cerebral amyloid angiopathy and also in another individual with early onset Alzheimer disease (ClinVar, PMID: 10821838, 28350801). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a well reported Dutch variant, HCHWA-D, and has been reported in multiple individuals with hereditary cerebral amyloid angiopathy and in individuals with Alzheimer's disease (ClinVar, PMID: 2111584, 10821838, 19061884, 23919771, 30868685). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Alzheimer disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 02, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect APP protein function (PMID: 19061884, 11441013, 10821838, 8610157). This variant has been observed in individual(s) with hereditary cerebral amyloid angiopathy and in individual(s) with Alzheimer's disease (PMID: 2111584, 23919771, 11004129). This variant has also been shown to segregate with disease. This variant is also known as p.Glu22Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 18087). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 693 of the APP protein (p.Glu693Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.;.;.;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N;N;N;N;.;N;N;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.010	D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D;D;D;D;T
Polyphen		0.99	D;D;P;P;.;.;D;.
Vest4		0.82
MutPred		0.94		Loss of stability (P = 0.0961);.;.;.;.;.;.;.;
MVP		0.98
MPC		1.2
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs63750579; hg19: chr21-27264168;