NM_000484.4(APP):c.2077G>C (p.Glu693Gln) AND Cerebral amyloid angiopathy, APP-related

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 2, 2022
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:: RCV002272024.4

Allele description [Variation Report for NM_000484.4(APP):c.2077G>C (p.Glu693Gln)]

NM_000484.4(APP):c.2077G>C (p.Glu693Gln)

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.2077G>C (p.Glu693Gln)

HGVS:

NC_000021.9:g.25891856C>G
NG_007376.2:g.284273G>C
NM_000484.4:c.2077G>CMANE SELECT
NM_001136016.3:c.2005G>C
NM_001136129.3:c.1684G>C
NM_001136130.3:c.1909G>C
NM_001136131.3:c.1747G>C
NM_001204301.2:c.2023G>C
NM_001204302.2:c.1966G>C
NM_001204303.2:c.1798G>C
NM_001385253.1:c.1909G>C
NM_201413.3:c.2020G>C
NM_201414.3:c.1852G>C
NP_000475.1:p.Glu693Gln
NP_001129488.1:p.Glu669Gln
NP_001129601.1:p.Glu562Gln
NP_001129602.1:p.Glu637Gln
NP_001129603.1:p.Glu583Gln
NP_001191230.1:p.Glu675Gln
NP_001191231.1:p.Glu656Gln
NP_001191232.1:p.Glu600Gln
NP_001372182.1:p.Glu637Gln
NP_958816.1:p.Glu674Gln
NP_958817.1:p.Glu618Gln
NC_000021.8:g.27264168C>G
NM_000484.3:c.2077G>C
P05067:p.Glu693Gln

Protein change:

E562Q; GLU693GLN

Links:

UniProtKB: P05067#VAR_000017; OMIM: 104760.0001; dbSNP: rs63750579

NCBI 1000 Genomes Browser:

rs63750579

Molecular consequence:

NM_000484.4:c.2077G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001136016.3:c.2005G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001136129.3:c.1684G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001136130.3:c.1909G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001136131.3:c.1747G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001204301.2:c.2023G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001204302.2:c.1966G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001204303.2:c.1798G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001385253.1:c.1909G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_201413.3:c.2020G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_201414.3:c.1852G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002557984	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 2111584, 10821838, 19061884, 23919771, 24524897, 24650794, 28350801, 30868685, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002557984

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 2, 2022)

germline

clinical testing

PubMed (9)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type.

Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B.

Science. 1990 Jun 1;248(4959):1124-6.

PubMed [citation]

PMID:: 2111584

Substitutions at codon 22 of Alzheimer's abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells.

Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J.

J Biol Chem. 2000 Sep 1;275(35):27110-6.

PubMed [citation]

PMID:: 10821838

See all PubMed Citations (9)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557984.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Toxic gain of function is a known mechanism of disease in this gene and is associated with Alzheimer disease 1, familial (MIM#104300) (PMID: 24524897). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. p.(Ala713Thr) has been reported to exhibit reduced penetrance (PMID: 28350801). (I) 0115 - Variants in this gene are known to have variable expressivity. Age of onset and disease progression can vary (GeneReviews; PMID: 24650794). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0703 – Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. An alternative change to a lysine has been reported in one individual with hereditary cerebral amyloid angiopathy and also in another individual with early onset Alzheimer disease (ClinVar, PMID: 10821838, 28350801). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a well reported Dutch variant, HCHWA-D, and has been reported in multiple individuals with hereditary cerebral amyloid angiopathy and in individuals with Alzheimer's disease (ClinVar, PMID: 2111584, 10821838, 19061884, 23919771, 30868685). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Sep 29, 2024

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Relating variation to medicine