Submissions for variant NM_000484.4(APP):c.2149G>A (p.Val717Ile)

dbSNP: rs63750264

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020308	SCV000935808	pathogenic	Alzheimer disease	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 717 of the APP protein (p.Val717Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with early-onset Alzheimer's disease (EOAD) (PMID: 24650794, 25138979, 27838006). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18088). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APP protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects APP function (PMID: 11978821, 19281847, 24524897). This variant disrupts the p.Val717 amino acid residue in APP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1925564, 15776278). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000084575	SCV001250462	pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000019714	SCV002557779	pathogenic	Alzheimer disease type 1	2022-02-02	criteria provided, single submitter	clinical testing	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 valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 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 within the transmembrane domain (DECIPHER; PMID: 24524897). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in more than ten unrelated families with Alzheimer disease. Asymptomatic carriers were noted in some; however, their ages were not provided to rule out reduced penetrance. Finally, this variant has been classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 24650794, 25138979, 27838006, 28350801). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Athena Diagnostics	RCV000084575	SCV002771849	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in an increased ratio of amyloid-beta-42 to amyloid-beta-40 (PMID: 8886002, 9328472, 11487570, 19281847). This variant is located in a region that is considered important for protein function and/or structure.
Fulgent Genetics, Fulgent Genetics	RCV002496421	SCV002807780	pathogenic	Cerebral amyloid angiopathy, APP-related; Alzheimer disease type 1	2021-12-10	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000019714	SCV004048033	pathogenic	Alzheimer disease type 1		criteria provided, single submitter	clinical testing	The missense c.2149G>A(p.Val717Ile) variant in APP gene has been reported in heterozygous state in individuals affected with Alzheimer's disease (Jiao, Bin et al.,2014). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects APP function (Herl, Lauren et al., 2009 ). The variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submitted to ClinVar as Pathogenic. The amino acid Val at position 717 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Val717Ile in APP is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993747	SCV004813609	pathogenic	Cerebral amyloid angiopathy, APP-related	2024-02-22	criteria provided, single submitter	clinical testing	Variant summary: APP c.2149G>A (p.Val717Ile) results in a conservative amino acid change located in the Beta-amyloid precursor protein C-terminal domain (IPR019543) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251364 control chromosomes (gnomAD). c.2149G>A has been reported in the literature in multiple individuals affected with early-onset Alzheimer's disease (EOAD) (examples: Noroozian_2014 and Zhang_2017). These data indicate that the variant is very likely to be associated with disease. Other variant(s) that disrupt this residue have been classified pathogenic in ClinVar. The following publications have been ascertained in the context of this evaluation (PMID: 27838006, 25138979). ClinVar contains an entry for this variant (Variation ID: 18088). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000084575	SCV005199568	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
OMIM	RCV000019714	SCV000040012	pathogenic	Alzheimer disease type 1	1996-10-23	no assertion criteria provided	literature only
GeneReviews	RCV000020308	SCV000040683	not provided	Alzheimer disease		no assertion provided	literature only
VIB Department of Molecular Genetics, University of Antwerp	RCV000084575	SCV000116711	not provided	not provided		no assertion provided	not provided