PDF (1.76 MB)

Search Results

APP (61)

Mutation	Clinical Phenotype	Pathogenicity	Neuropathology	Biological Effect	Genomic Position	Genomic Region	Mutation Type Codon Change	Research Models	Primary Papers
A201V	None, Parkinson's Disease Dementia	AD : Not Pathogenic	Not applicable.	Unknown; predicted tolerated in silico.	rs149995579	Coding Exon 5	Point, Missense GCG to GTG	0	Sassi et al., 2014
A235V	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 6	Point, Missense GCT to GTT	0	Nicolas et al., 2015
D243N	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 6	Point, Missense GAT to AAT	0	Nicolas et al., 2015
E246K	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown; predicted probably damaging in silico.	rs147485129	Coding Exon 6	Point, Missense GAG to AAG	0	Sala Frigerio et al., 2015
E296K	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 7	Point, Missense GAG to AAG	0	Nicolas et al., 2015
P299L	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 7	Point, Missense CCG to CTG	0	Nicolas et al., 2015
R468H	None	AD : Not Pathogenic	Not applicable.	Unknown.		Coding Exon 11	Point, Missense CGC to CAC	0	Schulte et al., 2015
A479S	None	AD : Not Pathogenic	Not applicable.	Unknown; predicted benign in silico.	rs143794560	Coding Exon 11	Point, Missense GCT to TCT	0	Sala Frigerio et al., 2015
K496Q	Alzheimer's Disease	AD : Unclear Pathogenicity	One reported carrier of this variant had autopsy-confirmed AD.	Unknown; predicted possibly damaging in silico.	rs201384815	Coding Exon 12	Point, Missense AAG to CAG	0	Sassi et al., 2014
A500T	None	AD : Not Pathogenic	Not applicable.	Unknown.	rs201547994	Coding Exon 12	Point, Missense GCA to ACA	0	Schulte et al., 2015
Y538H	Alzheimer's Disease	AD : Not Pathogenic	Neuropathology consistent with AD, but not thought to be attributed to this variant.	Decreased Aβ42 and Aβ40 in cells, without altering Aβ42/Aβ40 ratio.	rs45537238	Coding Exon 13	Point, Missense TAT to CAT	0	Sassi et al., 2014
V562I	None	AD : Not Pathogenic	Not applicable.	Unknown; predicted tolerated in silico.	rs199586073	Coding Exon 13	Point, Missense GTT to ATT	0	Sassi et al., 2014
E599K	None, Parkinson's Disease, Parkinson's Disease Dementia	AD : Not Pathogenic	Not applicable.	Unknown; predicted possibly damaging in silico.	rs140304729	Coding Exon 14	Point, Missense GAA to AAA	0	Sassi et al., 2014
T600M	None	AD : Not Pathogenic	Not applicable.	Unknown.	rs200088099	Coding Exon 14	Point, Missense ACG to ATG	0	Schulte et al., 2015
P620A	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 14	Point, Missense CCG to GCG	0	Nicolas et al., 2015
P620L	Alzheimer's Disease	AD : Not Pathogenic	One reported carrier of the variant had autopsy-confirmed AD.	Unknown; predicted tolerated in silico.		Coding Exon 14	Point, Missense CCG to CTG	0	Sassi et al., 2014
T663M	Parkinson's Disease Dementia	AD : Not Pathogenic, PDD : Unclear Pathogenicity	Unknown.	Unknown.	rs200260102	Coding Exon 16	Point, Missense ACG to ATG	0	Schulte et al., 2015
E665D	None	AD : Not Pathogenic	Not applicable.	Unknown.	rs63750363	Coding Exon 16	Point, Missense GAG to GAC	0	Peacock et al., 1994
V669L (Seoul)	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown, although MRI showed pronounced cerebral atrophy that included the hippocampus.	Unknown. Predicted benign by PolyPhen-2 and SIFT; neutral by PROVEAN.	rs1259157720	Coding Exon 16	Point, Missense GTG to CTG	0	Bagyinszky et al., 2019
KM670/671NL (Swedish)	Alzheimer's Disease	AD : Pathogenic	Generalized atrophy with sulcal widening and mild ventricular enlargement.	Increased total Aβ; unchanged Aβ42/Aβ40 ratio; increased production and secretion of Aβ42 and Aβ40.	rs63751263, rs63750445	Coding Exon 16	Point, Double AAG.ATG to AAT.CTG	73	Mullan et al., 1992
A673T (Icelandic)	None	AD : Protective	This variant is associated with minimal amyloid deposition and is thought to protect against amyloid pathology.	Reduced production of amyloidogenic Aβ peptides by about 40 percent. The Aβ generated is less prone to aggregation.	rs63750847	Coding Exon 16	Point, Missense GCA to ACA	1	Peacock et al., 1993; Jonsson et al., 2012
A673V	Alzheimer's Disease	AD : Pathogenic	Definite AD by CERAD criteria, with extensive deposition of Aβ and tau pathology (Braak stage VI). Cerebral amyloid angiopathy. Deposits contained high levels of Aβ40 and were noted to be unusually large, with few preamyloid deposits. Localization was frequently perivascular.	In vitro, A673V shifts β-secretase processing of APP toward the amyloidogenic pathway and increases Aβ aggregation; however, co-incubation of mutant and wild-type Aβ inhibits amyloidogenesis and toxicity.		Coding Exon 16	Point, Missense GCA to GTA	0	Di Fede et al., 2009
H677R (English)	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Accelerated oligomerization kinetics and greater cytotoxicity than wild-type Aβ.	rs63749953	Coding Exon 16	Point, Missense CAT to CGT	0	Janssen et al., 2003
D678H (Taiwanese)	Alzheimer's Disease	AD : Pathogenic	Unknown; SPECT imaging showed hypoperfusion in the bilateral parietal cortices and the left temporal lobe.	Increased Aβ42/Aβ40 ratio in conditioned media; increased secreted Aβ42 and Aβ40. When coincubated with Cu2+ and Zn2+, mutant Aβ exhibits increased metal ion binding and formation of ion-induced Aβ oligomers. Increased toxicity in vitro compared with wild-type Aβ42.		Coding Exon 16	Point, Missense GAC to CAC	0	Chen et al., 2012
D678N (Tottori)	Alzheimer's Disease	AD : Pathogenic	Marked cortical atrophy, bilateral hippocampal atrophy, absence of focal cerebral infarction or hemorrhagic lesions in heterozygous carrier; small lacunar lesions in temporoparietal cortex and subcortical white matter in homozygous carrier.	Accelerated oligomerization kinetics and greater cytotoxicity than wild-type Aβ.	rs63750064	Coding Exon 16	Point, Missense GAC to AAC	0	Wakutani et al., 2004
E682K (Leuven)	Alzheimer's Disease	AD : Pathogenic	Bilateral hippocampal volume loss; Cortical PiB uptake.	Significantly increased total Aβ and Aβ42/Aβ40 levels; Shifts BACE1 cleavage toward the β-site.		Coding Exon 16	Point, Missense GAA to AAA	0	Zhou et al., 2011
K687N	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed mild global brain atrophy without focal or vascular lesions. CSF biomarker profile consistent with AD, specifically elevated total tau and phosphorylated tau, along with reduced levels of Aβ1-42.	Reduces APP cleavage by α-secretase. Reduced production of total sAPP and especially sAPPα. Increased Aβ40 and Aβ42. Alone, mutant Aβ was less toxic to neuroblastoma cells than wild-type Aβ42, but mixed in equimolar amounts with wild-type, toxicity increased. Alone, mutant Aβ formed predominantly low-n oligomers in vitro, but mixed with wild-type Aβ, it aggregated into high-n oliogmers.		Coding Exon 16	Point, Missense AAA to AAT	0	Kaden et al., 2012
A692G (Flemish)	Alzheimer's Disease	AD : Pathogenic	β-amyloid deposition in the blood vessels of the brain; Numerous senile plaques; Dystrophic neurites; Congophilic angiopathy; Hemorrhagic infarction.	Increased secreted Aβ42 and Aβ40 in CHO, HEK-293, and H4 cells; Altered APP processing.	rs63750671	Coding Exon 17	Point, Missense GCA to GGA	0	Hendriks et al., 1992
E693del (Osaka, E693∆, E693delta)	Alzheimer's Disease	AD : Pathogenic	Unknown; remarkably low levels of amyloid by PiB-PET imaging.	Unchanged Aβ42/Aβ40 ratio; decreased Aβ42; decreased Aβ40; Mutant Aβ more resistant to degradation by neprilysin and insulin-degrading enzyme; Synthetic mutant Aβ had enhanced oligomerization but no fibrillization; Greater inhibition of LTP than wild-type Aβ.		Coding Exon 17	Deletion GAA to ---	1	Tomiyama et al., 2008
E693G (Arctic, E22G)	Alzheimer's Disease	AD : Pathogenic	No signs of strokes or vascular lesions by brain imaging; Neuritic plaques and neurofibrillary tangles.	Arctic Aβ40 forms protofibrils at an increased propensity and faster rate; Decreased proteolytic degradation of Aβ by neprilysin.	rs63751039	Coding Exon 17	Point, Missense GAA to GGA	6	Kamino et al., 1992; Nilsberth et al., 2001
E693K (Italian)	Cerebral Amyloid Angiopathy	CAA : Pathogenic	Small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts; Aβ immunoreactivity in vessel walls and neuropil; Absence of neurofibrillary changes and neuritic plaques.	Reduced Aβ42/Aβ40 ratio; decreased Aβ42; comparable Aβ40 to wild-type APP.	rs63750579	Coding Exon 17	Point, Missense GAA to AAA	0	Tagliavini et al., 1999; Bugiani et al., 2010
E693Q (Dutch)	Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type	CAA : Pathogenic	Extensive amyloid deposition in the cerebral vasculature; Hemorrhages; Some diffuse plaques in brain parenchyma.	Accelerates Aβ aggregation in vitro, increasing fibril formation; Alters the processing of APP, increasing the relative quantities of Aβ beginning at Asp1, Val18, and Phe19.	rs63750579	Coding Exon 17	Point, Missense GAA to CAA	4	Levy et al., 1990; Van Broeckhoven et al., 1990; Fernandez-Madrid et al., 1991
D694N (Iowa)	Alzheimer's Disease, Cerebral Amyloid Angiopathy	AD : Pathogenic, CAA : Pathogenic	Extensive cerebral amyloid angiopathy; Widespread neurofibrillary tangles; Abundant Aβ40 in plaques; Hemorrhagic lesions; Cortical calcifications in the occipital lobe.	Increased fibrillogenesis of the Aβ peptide; Greater Aβ-induced toxicity.	rs63749810	Coding Exon 17	Point, Missense GAT to AAT	2	Grabowski et al., 2001
V695M	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Predicted to be tolerated by SIFT and to be benign by PolyPhen-2; classified as disease-causing by Mutation Taster.		Coding Exon 17	Point, Missense GTG to ATG	0	Gao et al., 2019
L705V	Cerebral Amyloid Angiopathy	CAA : Pathogenic	Severe CAA; Hemorrhages originating from affected vessels; “Vessel-within-vessel” morphology; Absence of parenchymal amyloid deposits and neurofibrillary tangles.	Unknown.	rs63750921	Coding Exon 17	Point, Missense CTC to GTC	0	Obici et al., 2005
G708G	None	AD : Not Pathogenic	Not applicable.	Unknown.	rs148888161	Coding Exon 17	Point, Silent GGC to GGT	0	Balbín et al., 1992
G709S	Parkinson's Disease Dementia	AD : Not Pathogenic, PDD : Unclear Pathogenicity	Unknown.	Unknown.	rs201269325	Coding Exon 17	Point, Missense GGT to AGT	0	Schulte et al., 2015
A713T	Alzheimer's Disease, Cerebral Amyloid Angiopathy, None	AD : Unclear Pathogenicity, CAA : Unclear Pathogenicity	Variable: Generalized atrophy of the cerebral cortex; Widespread neurofibrillary tangles; Neuritic plaques; Variable cerebral amyloid angiopathy.	Unchanged Aβ42/Aβ40 ratio in postmortem brain.	rs63750066	Coding Exon 17	Point, Missense GCG to ACG	0	Carter et al., 1992; Armstrong et al., 2004
A713V	None	AD : Not Pathogenic	Not applicable.	Decreased Aβ42 and Aβ40 secretion in cells; no effect on Aβ42/Aβ40 ratio.	rs1800557	Coding Exon 17	Point, Missense GCG to GTG	0	Jones et al., 1992
T714A (Iranian)	Alzheimer's Disease	AD : Pathogenic	Progressive cortical atrophy; White matter lesions.	Unknown.	rs63750643	Coding Exon 17	Point, Missense ACA to GCA	0	Pasalar et al., 2002
T714I (Austrian)	Alzheimer's Disease	AD : Pathogenic	Extensive neuronal loss; Diffuse gliosis; Neurofibrillary tangles; Amyloid plaques including diffuse "cloudy" plaques.	Increased Aβ42/Aβ40 ratio (about 11-fold); increased Aβ42; decreased Aβ40.	rs63750973	Coding Exon 17	Point, Missense ACA to ATA	1	Kumar-Singh et al., 2000
V715A (German)	Alzheimer's Disease	AD : Pathogenic	Hypoperfusion in the parieto-occipital region.	Increased Aβ42/Aβ40 ratio.	rs63750868	Coding Exon 17	Point, Missense GTG to GCG	0	Cruts et al., 2003
V715M (French)	Alzheimer's Disease	AD : Pathogenic	Progressive cortical atrophy; Hypometabolism.	Decreased total Aβ; unchanged Aβ42; significantly decreased Aβ40.	rs63750734	Coding Exon 17	Point, Missense GTG to ATG	0	Ancolio et al., 1999
I716F (Iberian)	Alzheimer's Disease	AD : Pathogenic	Extensive mixed neuropathology, including neurofibrillary changes, amyloid deposits, and Lewy bodies.	Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40; Increased APP C-terminal fragments; Decreased production of APP intracellular domain.		Coding Exon 17	Point, Missense ATC to TTC	3	Guerreiro et al., 2010
I716M	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed mild bilateral hippocampal atrophy.	Unknown; predicted damaging in silico.		Coding Exon 17	Point, Missense ATC to ATG	0	Blauwendraat et al., 2016
I716T	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown.	rs63750851	Coding Exon 17	Point, Missense ATC to ACC	0	Terreni et al., 2002
I716V (Florida)	Alzheimer's Disease	AD : Pathogenic	Diffuse cortical atrophy, most prominant in the left anterior temporal lobe.	Increased Aβ42(43)/Aβ40 ratio; increased Aβ42(43).	rs63750399	Coding Exon 17	Point, Missense ATC to GTC	11	Eckman et al., 1997
V717F (Indiana)	Alzheimer's Disease	AD : Pathogenic	Unknown.	Increased Aβ42/Aβ40 ratio.	rs63750264	Coding Exon 17	Point, Missense GTC to TTC	13	Murrell et al., 1991
V717G	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD in at least one case.	Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.	rs63749964	Coding Exon 17	Point, Missense GTC to GGC	0	Chartier-Harlin et al., 1991
V717I (London)	Alzheimer's Disease	AD : Pathogenic	Variable: some reports of mild amyloid angiopathy and cortical and brainstem Lewy bodies, along with numerous plaques and tangles.	Increased Aβ42/Aβ40 ratio; increased Aβ42; little effect on Aβ40.	rs63750264	Coding Exon 17	Point, Missense GTC to ATC	23	Goate et al., 1991
V717L	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI in the Japanese family showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices.	Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.	rs63750264	Coding Exon 17	Point, Missense GTC to CTC	0	Murrell et al., 2000
T719N	Alzheimer's Disease	AD : Pathogenic	Unknown.	In a heterologous expression system, the T719N mutation led to increased levels of Aβ42 and an elevated Aβ42:Aβ40 ratio, compared with wild-type APP.		Coding Exon 17	Point, Missense ACC to AAC	0	Hsu et al., 2018
T719P	Alzheimer's Disease	AD : Pathogenic	Unknown; atrophy of the temporal lobes by MRI.	Reduced total Aβ in CSF, especially Aβ1-40 and Aβ1-42 with a relative increase in Aβ1-38.		Coding Exon 17	Point, Missense ACC to CCC	0	Ghidoni et al., 2009
M722K	Alzheimer's Disease, None	AD : Pathogenic	Unknown; MRI of the proband at age 42 showed moderate cerebral atrophy, especially in the hippocampus.	Increase Aβ42/Aβ40 ratio; increased Aβ42; unchanged Aβ40; More phospho-tau.		Coding Exon 17	Point, Missense ATG to AAG	0	Wang et al., 2015
L723P (Australian)	Alzheimer's Disease	AD : Pathogenic	Unknown.	Increased Aβ42 in CHO cells.	rs63751122	Coding Exon 17	Point, Missense CTG to CCG	0	Kwok et al., 2000
K724N (Belgian)	Alzheimer's Disease	AD : Pathogenic	Significant amyloid across the cerebral cortex as measured by PiB-PET.	Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.	rs63750151	Coding Exon 17	Point, Missense AAG to AAC	0	Theuns et al., 2006
H733P	None	AD : Not Pathogenic	Not applicable.	Unknown.		Coding Exon 17	Point, Missense CAT to CCT	0	Guerreiro et al., 2010
IVS17 83-88delAAGTAT	Alzheimer's Disease, None	AD : Unclear Pathogenicity	Unknown; at least one affected deletion carrier had neuropathology consistent with AD.	Unknown; deletion does not appear to affect APP splicing.	rs367709245	Non-Coding Intron 17	Deletion	0	Kamino et al., 1992
c.*18 C>T	Cerebral Amyloid Angiopathy	CAA : Unclear Pathogenicity	Unknown; imaging showed an ischemic stroke in the right middle cerebral artery and hematomas in the right temporal and parietal lobes. MRI showed numerous cortical microbleeds and white-matter hyperintensities.	Unknown.	rs201729239	Non-Coding 3' UTR	Point	0	Nicolas et al., 2015
c.331_332del	Cerebral Amyloid Angiopathy	CAA : Pathogenic	Unknown; imaging revealed multiple subarachnoid hemorrhages and hematomas in the temporal, frontal, and parietal regions of the cortex, as well as diffuse superficial siderosis, cortical microbleeds, and white matter hyperintensities.	This deletion of two base pairs (TA) occurs in a highly conserved region of the UTR. When cloned into a luciferase reporter, the variant increased APP expression (~1.5-fold over WT). APP upregulation was at least partially attributable to changes in miRNA binding.		Non-Coding 3' UTR	Deletion	0	Nicolas et al., 2015
c.*372 A>G	Cerebral Amyloid Angiopathy	CAA : Not Pathogenic	Unknown; at least two mutation carriers had hemorrhages and microbleeds consistent with CAA. However, this variant has also been detected in controls.	Unknown.	rs187940037	Non-Coding 3' UTR	Point	0	Nicolas et al., 2015