rs63750066

Variant names:

• chr21-25891796-C-T
• rs63750066
• NM_000484.4:c.2137G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PM1 PM5 PP3_Moderate PP5_Very_Strong BS2_Supporting

The NM_000484.4(APP):​c.2137G>A​(p.Ala713Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A713V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: APP NM_000484.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.51
• Publications: 60 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 13 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_000484.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-25891795-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3690355.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 21-25891796-C-T is Pathogenic according to our data. Variant chr21-25891796-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 18094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4	c.2137G>A	p.Ala713Thr	missense_variant	Exon 17 of 18	ENST00000346798.8	NP_000475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8	c.2137G>A	p.Ala713Thr	missense_variant	Exon 17 of 18	1	NM_000484.4	ENSP00000284981.4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000955 AC: 24 AN: 251384 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111980

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000276 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alzheimer disease Pathogenic:2

Dec 01, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APP c.2137G>A (p.Ala713Thr) results in a non-conservative amino acid change located in the Amyloidogenic glycoprotein, amyloid-beta peptide (IPR013803) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251384 control chromosomes with 24 heterozygotes in GnomAD. c.2137G>A has been reported in the literature in multiple individuals affected with Autosomal dominant Alzheimer Disease and/or cerebrovascular lesion (examples, Carter_1992, Rossi_2004, Armstrong_2004, Bernardi_2009, Moro_2012, Pera_2013, Conidi_2014, Barber_2016, Lanoiselee_2017). Most of patients had a family history of Alzheimer Disease, and the clinical presentation featured with a progressive cognitive decline with a wide range of onset ages (49 to 85 years-old). Particularly, the variant was reported at a homozygous state in 3 patients from a consanguineous family with Alzheimer Disease and cerebrovascular lesion, and the clinical outcome and disease onset were not different from the heterozygous carriers from the same family (Conidi_2014). Meanwhile, multiple asymptomatic carriers were reported, including one 88-years-old woman (example, Carter_1992). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, which suggest this variant resulted in a significant increase in the Beta amyloid 42/40 ratio compared with WT in N2A cells via ELISA, the total amount of Beta amyloid was however reduced (Hsu_2020). Such results does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 15488330, 24278680, 19363265, 1303275, 25948718, 32087291, 28350801, 23143229, 23224319, 15365148). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=3, VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 713 of the APP protein (p.Ala713Thr). This variant is present in population databases (rs63750066, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Alzheimer's disease and a positive family history of the disorder, although many of these individuals did not have early onset of disease. In addition, it has been reported in the heterozygous state in 2 affected individuals and the homozygous state in 3 affected individuals from a single consanguineous family (PMID: 15365148, 15488330, 19363265, 23224319, 25948718, 26803359, 28350801). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18094). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt APP protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APP function (PMID: 29459625). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1 Other:1

May 15, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While the frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene, it is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org), PMID: 1303275, 19363265, 26803359, 29859640, 30279455, 32917274). This variant has been identified in at least one individual with clinical features associated with this gene. This variant associates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 29459625, 32087291) -

-

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Primary degenerative dementia of the Alzheimer type, presenile onset Pathogenic:1

Jan 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala713Thr variant in APP has been reported in 16 probands with Alzheimer disease and segregated in 8 affected family members (Carter 1992, Rossi 2004, Amstrong 2004, Bernandi 2009, Pera 2013, Conidi 2015, Barber 2016, Lanoiselee 2017, Koriath 2018). In one family with 6 affected individuals, all 3 living affected harbored the variant and 6 of 24 unaffected members (1 over the age of 65) carried the variant (Rossi 2004). In another family the variant was also present in 5 unaffected members (3 over the age of 62) (Carter 1992). In a third family there was one additional affected family member, however, the carrier status was not determined (Amstrong 2004). In 3 additional families the probands presented with late onset Alzheimer disease associated with cerebrovascular lesions. Other family members were reportedly affected with dementia; however their carrier status for the p.Ala713Thr variant was not documented (Bernandi 2009). In another multigenerational family, the variant was found in 5 patients (2 heterozygous and 3 homozygous) and in 6 asymptomatic at risk individuals (Conidi 2015). This variant has also been identified in 21/34414 (0.061%) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID 18094). Computational analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant exists in a region of the protein where other pathogenic variants cluster and is a known site for protein cleavage. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala713Thr variant is likely pathogenic albeit with reduced and age-related penetrance. ACMG/AMP Criteria applied:PP1_Strong, PM1, PP3. -

Alzheimer disease type 1 Pathogenic:1

Sep 14, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cerebral amyloid angiopathy, APP-related Pathogenic:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0101 – Toxic gain of function is a known mechanism of disease in this gene and is associated with cerebral amyloid angiopathy (MIM#605714) and familial Alzheimer disease 1 (MIM#104300) (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Specifically, the p.(Ala713Thr) variant has been reported to have incomplete penetrance as there are unaffected carriers of this variant (PMID: 28350801; gnomAD). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable ages of onset and differences in disease progression have been reported (PMID: 24650794; GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (25 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Ala713Val): 13 heterozygotes, 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). The amino acid residue is also a gamma-secretase cleavage site (UniProt). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Ala713Val) has been described as ‘not pathogenic’ in the literature, with no increase in the ABeta42/40 ratio or ABeta42 demonstrated for this variant (PMIDs: 32087291, 31011484). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least ten individuals with mild cognitive impairment, progressive dementia and Alzheimer disease including several large families with Alzheimer disease (PMIDs: 15488330, 15365148, 23143229, 25948718, 28350801, 32908482). It should be noted that this variant was recently classified as a risk factor; however limited justification was provided for the classification (PMID: 32087291). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Injection of human brain extracts from a deceased individual carrying the p.(Ala713Thr) variant into mice resulted in brain amyloidosis with higher ABeta levels detected in the insoluble faction of brain homogenates compared to control mice (PMID: 29459625). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;.;.
PhyloP100		7.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D;D;D;D;.;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0050	D;D;D;D;.;D;D;T
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.;D;.
Vest4		0.91
MutPred		0.91		Loss of helix (P = 0.028);.;.;.;.;.;.;.;
MVP		0.99
MPC		1.2
ClinPred		0.64	D
GERP RS		5.7
Varity_R		0.83
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63750066; hg19: chr21-27264108;