NM_000484.4(APP):c.2137G>A (p.Ala713Thr) AND Alzheimer disease

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 1, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000547582.7

Allele description [Variation Report for NM_000484.4(APP):c.2137G>A (p.Ala713Thr)]

NM_000484.4(APP):c.2137G>A (p.Ala713Thr)

Gene:

APP:amyloid beta precursor protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q21.3

Genomic location:

Preferred name:

NM_000484.4(APP):c.2137G>A (p.Ala713Thr)

HGVS:

NC_000021.9:g.25891796C>T
NG_007376.2:g.284333G>A
NM_000484.4:c.2137G>AMANE SELECT
NM_001136016.3:c.2065G>A
NM_001136129.3:c.1744G>A
NM_001136130.3:c.1969G>A
NM_001136131.3:c.1807G>A
NM_001204301.2:c.2083G>A
NM_001204302.2:c.2026G>A
NM_001204303.2:c.1858G>A
NM_001385253.1:c.1969G>A
NM_201413.3:c.2080G>A
NM_201414.3:c.1912G>A
NP_000475.1:p.Ala713Thr
NP_001129488.1:p.Ala689Thr
NP_001129601.1:p.Ala582Thr
NP_001129602.1:p.Ala657Thr
NP_001129603.1:p.Ala603Thr
NP_001191230.1:p.Ala695Thr
NP_001191231.1:p.Ala676Thr
NP_001191232.1:p.Ala620Thr
NP_001372182.1:p.Ala657Thr
NP_958816.1:p.Ala694Thr
NP_958817.1:p.Ala638Thr
NC_000021.8:g.27264108C>T
NG_007376.1:g.284025G>A
NM_000484.3:c.2137G>A
P05067:p.Ala713Thr

Protein change:

A582T; ALA713THR

Links:

UniProtKB: P05067#VAR_000019; OMIM: 104760.0009; dbSNP: rs63750066

NCBI 1000 Genomes Browser:

rs63750066

Molecular consequence:

NM_000484.4:c.2137G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136016.3:c.2065G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136129.3:c.1744G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136130.3:c.1969G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136131.3:c.1807G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204301.2:c.2083G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204302.2:c.2026G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204303.2:c.1858G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001385253.1:c.1969G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201413.3:c.2080G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201414.3:c.1912G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Alzheimer disease
Synonyms:: Presenile and senile dementia; Alzheimer's disease
Identifiers:: MONDO: MONDO:0004975; MeSH: D000544; MedGen: C0002395; Orphanet: 1020; Human Phenotype Ontology: HP:0002511

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Algimonas porphyrae strain LMG 26424 chromosome, complete genome
Algimonas porphyrae strain LMG 26424 chromosome, complete genome
gi|2791377754|ref|NZ_CP163424.1|

Nucleotide
basic helix-loop-helix (bHLH) DNA-binding superfamily protein [Arabidopsis thali...
basic helix-loop-helix (bHLH) DNA-binding superfamily protein [Arabidopsis thaliana]
gi|42569863|ref|NP_181757.2|

Protein
cytochrome oxidase subunit 1, partial (mitochondrion) [Labeo rohita]
cytochrome oxidase subunit 1, partial (mitochondrion) [Labeo rohita]
gi|1315444058|gb|AUG84049.1|

Protein
Inherited neurodegenerative disorder
Inherited neurodegenerative disorder

MedGen
Microcephaly 14, primary, autosomal recessive
Microcephaly 14, primary, autosomal recessive

MedGen

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000622178	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 21, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 29459625, 15365148, 15488330, 19363265, 23224319, 25948718, 26803359, 28350801, 28492532
SCV004241831	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 1, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 28350801, 15488330, 24278680, 19363265, 1303275, 25948718, 32087291, 23143229, 23224319, 15365148 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000622178

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 21, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV004241831

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Dec 1, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular subtypes of Alzheimer's disease.

Di Fede G, Catania M, Maderna E, Ghidoni R, Benussi L, Tonoli E, Giaccone G, Moda F, Paterlini A, Campagnani I, Sorrentino S, Colombo L, Kubis A, Bistaffa E, Ghetti B, Tagliavini F.

Sci Rep. 2018 Feb 19;8(1):3269. doi: 10.1038/s41598-018-21641-1.

PubMed [citation]

PMID:: 29459625
PMCID:: PMC5818536

Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease.

Barber IS, García-Cárdenas JM, Sakdapanichkul C, Deacon C, Zapata Erazo G, Guerreiro R, Bras J, Hernandez D, Singleton A, Guetta-Baranes T, Braae A, Clement N, Patel T, Brookes K, Medway C, Chappell S, Mann DM; ARUK Consortium., Morgan K.

Neurobiol Aging. 2016 Mar;39:220.e1-7. doi: 10.1016/j.neurobiolaging.2015.12.011. Epub 2015 Dec 29.

PubMed [citation]

PMID:: 26803359
PMCID:: PMC5155438

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000622178.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APP function (PMID: 29459625). 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. ClinVar contains an entry for this variant (Variation ID: 18094). 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. This variant is present in population databases (rs63750066, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004241831.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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