VCV000018097.5 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 18097 Accession: VCV000018097.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q21.3 21: 25891790 (GRCh38) [ NCBI UCSC ] 21: 27264102 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 20, 2014	Feb 14, 2024	Aug 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000484.4:c.2143G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000475.1:p.Val715Met	missense
NM_001136016.3:c.2071G>A	NP_001129488.1:p.Val691Met	missense
NM_001136129.3:c.1750G>A	NP_001129601.1:p.Val584Met	missense
NM_001136130.3:c.1975G>A	NP_001129602.1:p.Val659Met	missense
NM_001136131.3:c.1813G>A	NP_001129603.1:p.Val605Met	missense
NM_001204301.2:c.2089G>A	NP_001191230.1:p.Val697Met	missense
NM_001204302.2:c.2032G>A	NP_001191231.1:p.Val678Met	missense
NM_001204303.2:c.1864G>A	NP_001191232.1:p.Val622Met	missense
NM_001385253.1:c.1975G>A	NP_001372182.1:p.Val659Met	missense
NM_201413.3:c.2086G>A	NP_958816.1:p.Val696Met	missense
NM_201414.3:c.1918G>A	NP_958817.1:p.Val640Met	missense
NC_000021.9:g.25891790C>T
NC_000021.8:g.27264102C>T
NG_007376.2:g.284339G>A
	P05067:p.Val715Met

... more HGVS ... less HGVS

Protein change

V715M, V622M, V640M, V678M, V584M, V691M, V697M, V605M, V659M, V696M

Other names

Canonical SPDI

NC_000021.9:25891789:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA127800 UniProtKB: P05067#VAR_010108 OMIM: 104760.0012 dbSNP: rs63750734 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
APP		No evidence available	Sufficient evidence for dosage pathogenicity	GRCh38 GRCh37	462	573

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Alzheimer disease type 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 5, 2023	RCV000019724.34
not provided	Likely pathogenic (2)	criteria provided, single submitter	Jun 23, 2017	RCV000084570.5
Alzheimer disease	Pathogenic (1)	criteria provided, single submitter	Aug 2, 2023	RCV003509483.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alzheimer disease type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV003925659.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Comment: Criteria applied: PS3,PS4_MOD,PM1,PM5,PM2_SUP,PP3 Clinical Features: Alzheimer disease (present) , Dementia (present) Sex: female
Likely pathogenic (Jun 23, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000612389.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014	Publications: PubMed (9) PubMed: 10441572‚ 20452985‚ 10097173‚ 24390130‚ 24677022‚ 18437002‚ 11487570‚ 24694184‚ 23515184
Pathogenic (Mar 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Alzheimer disease type 1 Affected status: yes Allele origin: germline	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University Accession: SCV003932785.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Publications: PubMed (1) PubMed: 11487570 Comment: This case has this variant as heterozygous Number of individuals with the variant: 1 Age: 40-49 years Sex: female Ethnicity/Population group: Caucasian Geographic origin: Anatolian Peninsula
Pathogenic (Aug 02, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Alzheimer disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004297369.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 10441572‚ 18437002‚ 10097173‚ 11487570‚ 20452985 Comment: This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is … (more) This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 715 of the APP protein (p.Val715Met). This missense change has been observed in individuals with early-onset Alzheimer disease (PMID: 10441572, 18437002; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects APP function (PMID: 10097173, 11487570, 20452985). 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: 18097). (less)
Pathogenic (Sep 01, 1999)	no assertion criteria provided Method: literature only	ALZHEIMER DISEASE, FAMILIAL, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000040022.3 First in ClinVar: Apr 04, 2013 Last updated: May 21, 2018	Publications: PubMed (2) PubMed: 10097173‚ 10441572 Comment on evidence: 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 … (more) 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. (less)
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	VIB Department of Molecular Genetics, University of Antwerp Accession: SCV000116706.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg18&id=ADM_71

Comment:

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 715 of the APP protein (p.Val715Met). This missense change has been observed in individuals with early-onset Alzheimer disease (PMID: 10441572, 18437002; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects APP function (PMID: 10097173, 11487570, 20452985). 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: 18097).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Abundance of Aβ₅-x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer's disease.	Guzmán EA	Molecular neurodegeneration	2014	PMID: 24694184
Blepharospasm in familial AD secondary to an APP mutation (V715M).	Nan SJ	Acta neurologica Belgica	2014	PMID: 24677022
Familial Alzheimer's mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site.	Chen W	Nature communications	2014	PMID: 24390130
Comparable dimerization found in wildtype and familial Alzheimer's disease amyloid precursor protein mutants.	So PP	American journal of neurodegenerative disease	2013	PMID: 23515184
Aberrant amyloid precursor protein (APP) processing in hereditary forms of Alzheimer disease caused by APP familial Alzheimer disease mutations can be rescued by mutations in the APP GxxxG motif.	Munter LM	The Journal of biological chemistry	2010	PMID: 20452985
Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer's disease.	Park HK	Journal of Korean medical science	2008	PMID: 18437002
Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability.	De Jonghe C	Human molecular genetics	2001	PMID: 11487570
Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.	Campion D	American journal of human genetics	1999	PMID: 10441572
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	Proceedings of the National Academy of Sciences of the United States of America	1999	PMID: 10097173

Text-mined citations for rs63750734 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63750734 ...