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NM_000484.4(APP):c.2149G>A (p.Val717Ile) AND Cerebral amyloid angiopathy, APP-related

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 22, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003993747.1

Allele description [Variation Report for NM_000484.4(APP):c.2149G>A (p.Val717Ile)]

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

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.2149G>A (p.Val717Ile)
HGVS:
  • NC_000021.9:g.25891784C>T
  • NG_007376.2:g.284345G>A
  • NM_000484.4:c.2149G>AMANE SELECT
  • NM_001136016.3:c.2077G>A
  • NM_001136129.3:c.1756G>A
  • NM_001136130.3:c.1981G>A
  • NM_001136131.3:c.1819G>A
  • NM_001204301.2:c.2095G>A
  • NM_001204302.2:c.2038G>A
  • NM_001204303.2:c.1870G>A
  • NM_001385253.1:c.1981G>A
  • NM_201413.3:c.2092G>A
  • NM_201414.3:c.1924G>A
  • NP_000475.1:p.Val717Ile
  • NP_001129488.1:p.Val693Ile
  • NP_001129601.1:p.Val586Ile
  • NP_001129602.1:p.Val661Ile
  • NP_001129603.1:p.Val607Ile
  • NP_001191230.1:p.Val699Ile
  • NP_001191231.1:p.Val680Ile
  • NP_001191232.1:p.Val624Ile
  • NP_001372182.1:p.Val661Ile
  • NP_958816.1:p.Val698Ile
  • NP_958817.1:p.Val642Ile
  • NC_000021.8:g.27264096C>T
  • NG_007376.1:g.284037G>A
  • NM_000484.2:c.2149G>A
  • NM_000484.3:c.2149G>A
  • P05067:p.Val717Ile
Protein change:
V586I; VAL717ILE
Links:
UniProtKB: P05067#VAR_000021; OMIM: 104760.0002; dbSNP: rs63750264
NCBI 1000 Genomes Browser:
rs63750264
Molecular consequence:
  • NM_000484.4:c.2149G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136016.3:c.2077G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136129.3:c.1756G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136130.3:c.1981G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001136131.3:c.1819G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204301.2:c.2095G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204302.2:c.2038G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204303.2:c.1870G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001385253.1:c.1981G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_201413.3:c.2092G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_201414.3:c.1924G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cerebral amyloid angiopathy, APP-related
Synonyms:
AMYLOIDOSIS, CEREBROARTERIAL, APP-RELATED; Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants
Identifiers:
MONDO: MONDO:0011583; MedGen: C2751536; Orphanet: 100006; Orphanet: 324703; Orphanet: 324708; Orphanet: 324713; Orphanet: 324718; Orphanet: 324723; Orphanet: 85458; OMIM: 605714

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004813609Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Feb 22, 2024) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Early-onset Alzheimer's disease in two Iranian families: a genetic study.

Noroozian M, Azadfar P, Akbari L, Sadeghi A, Houshmand M, Vousooghi N, Zarrindast MR, Minagar A.

Dement Geriatr Cogn Disord. 2014;38(5-6):330-6. doi: 10.1159/000358232. Epub 2014 Aug 14.

PubMed [citation]
PMID:
25138979

Clinical characterization of an APP mutation (V717I) in five Han Chinese families with early-onset Alzheimer's disease.

Zhang G, Xie Y, Wang W, Feng X, Jia J.

J Neurol Sci. 2017 Jan 15;372:379-386. doi: 10.1016/j.jns.2016.10.039. Epub 2016 Oct 28.

PubMed [citation]
PMID:
27838006

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813609.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024