NM_000484.4(APP):c.2143G>A (p.Val715Met) AND Alzheimer disease type 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 5, 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:: RCV000019724.34

Allele description [Variation Report for NM_000484.4(APP):c.2143G>A (p.Val715Met)]

NM_000484.4(APP):c.2143G>A (p.Val715Met)

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.2143G>A (p.Val715Met)

HGVS:

NC_000021.9:g.25891790C>T
NG_007376.2:g.284339G>A
NM_000484.4:c.2143G>AMANE SELECT
NM_001136016.3:c.2071G>A
NM_001136129.3:c.1750G>A
NM_001136130.3:c.1975G>A
NM_001136131.3:c.1813G>A
NM_001204301.2:c.2089G>A
NM_001204302.2:c.2032G>A
NM_001204303.2:c.1864G>A
NM_001385253.1:c.1975G>A
NM_201413.3:c.2086G>A
NM_201414.3:c.1918G>A
NP_000475.1:p.Val715Met
NP_001129488.1:p.Val691Met
NP_001129601.1:p.Val584Met
NP_001129602.1:p.Val659Met
NP_001129603.1:p.Val605Met
NP_001191230.1:p.Val697Met
NP_001191231.1:p.Val678Met
NP_001191232.1:p.Val622Met
NP_001372182.1:p.Val659Met
NP_958816.1:p.Val696Met
NP_958817.1:p.Val640Met
NC_000021.8:g.27264102C>T
NG_007376.1:g.284031G>A
NM_000484.3:c.2143G>A
P05067:p.Val715Met

Protein change:

V584M; VAL715MET

Links:

UniProtKB: P05067#VAR_010108; OMIM: 104760.0012; dbSNP: rs63750734

NCBI 1000 Genomes Browser:

rs63750734

Molecular consequence:

NM_000484.4:c.2143G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136016.3:c.2071G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136129.3:c.1750G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136130.3:c.1975G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136131.3:c.1813G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204301.2:c.2089G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204302.2:c.2032G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204303.2:c.1864G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001385253.1:c.1975G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201413.3:c.2086G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_201414.3:c.1918G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Alzheimer disease type 1 (AD1)
Synonyms:: ALZHEIMER DISEASE, FAMILIAL, 1; ALZHEIMER DISEASE, FAMILIAL, 1, AUTOSOMAL RECESSIVE
Identifiers:: MONDO: MONDO:0007088; MedGen: C1863052; OMIM: 104300

Recent activity

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Synthetic construct Mus musculus clone IMAGE:100016044, MGC:184343 forkhead box ...
Synthetic construct Mus musculus clone IMAGE:100016044, MGC:184343 forkhead box D3 (Foxd3) mRNA, encodes complete protein
gi|157170015|gb|BC152802.1|

Nucleotide
ELOVL4 [Dromaius novaehollandiae]
ELOVL4 [Dromaius novaehollandiae]
Gene ID:112995862

Gene
GSM6435894[Accession] (4)
GEO DataSets

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000040022	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 1999)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10097173, 10441572
SCV003925659	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 5, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003932785	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 21, 2023)	germline	research	PubMed (2) [See all records that cite these PMIDs] 11487570, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000040022

OMIM

no assertion criteria provided

Pathogenic
(Sep 1, 1999)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV003925659

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 5, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003932785

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 21, 2023)

germline

research

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease.

Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frébourg T, Checler F.

Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4119-24.

PubMed [citation]

PMID:: 10097173
PMCID:: PMC22430

Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.

Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T.

Am J Hum Genet. 1999 Sep;65(3):664-70.

PubMed [citation]

PMID:: 10441572
PMCID:: PMC1377972

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000040022.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In affected members of a family with early-onset AD (104300), Ancolio et al. (1999) identified a mutation in the APP gene, resulting in a val715-to-met (V715M) substitution. Overexpression of V715M in human HEK293 cells and murine neurons reduced total A-beta production and increased the recovery of the physiologically secreted product, APP-alpha. The V715M mutation significantly reduced A-beta-40 secretion without affecting A-beta-42 production in HEK293 cells. However, a marked increase in N-terminally truncated A-beta ending at position 42 was observed, whereas its counterpart ending at position 40 was not affected. These results suggested that, in some cases, familial AD may be associated with a reduction in the overall production of A-beta, but may be caused by increased production of truncated forms of A-beta ending at position 42. This family with the V715M mutation was also reported by Campion et al. (1999), the same family having been ascertained through a population-based survey of early-onset Alzheimer disease.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV003925659.1

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

Description

Criteria applied: PS3,PS4_MOD,PM1,PM5,PM2_SUP,PP3

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

From Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University, SCV003932785.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	research	PubMed (2)

Description

This case has this variant as heterozygous

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

Last Updated: Sep 29, 2024

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