NM_000484.4(APP):c.2030A>G (p.His677Arg) AND APP-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 16, 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:: RCV003430663.5

Allele description [Variation Report for NM_000484.4(APP):c.2030A>G (p.His677Arg)]

NM_000484.4(APP):c.2030A>G (p.His677Arg)

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.2030A>G (p.His677Arg)

HGVS:

NC_000021.9:g.25897607T>C
NG_007376.2:g.278522A>G
NM_000484.3:c.2030A>G
NM_000484.4:c.2030A>GMANE SELECT
NM_001136016.3:c.1958A>G
NM_001136129.3:c.1637A>G
NM_001136130.3:c.1862A>G
NM_001136131.3:c.1700A>G
NM_001204301.2:c.1976A>G
NM_001204302.2:c.1919A>G
NM_001204303.2:c.1751A>G
NM_001385253.1:c.1862A>G
NM_201413.3:c.1973A>G
NM_201414.3:c.1805A>G
NP_000475.1:p.His677Arg
NP_001129488.1:p.His653Arg
NP_001129601.1:p.His546Arg
NP_001129602.1:p.His621Arg
NP_001129603.1:p.His567Arg
NP_001191230.1:p.His659Arg
NP_001191231.1:p.His640Arg
NP_001191232.1:p.His584Arg
NP_001372182.1:p.His621Arg
NP_958816.1:p.His658Arg
NP_958817.1:p.His602Arg
NC_000021.8:g.27269919T>C
NG_007376.1:g.278214A>G

Protein change:

H546R

Links:

dbSNP: rs63749953

NCBI 1000 Genomes Browser:

rs63749953

Molecular consequence:

NM_000484.4:c.2030A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001136016.3:c.1958A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001136129.3:c.1637A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001136130.3:c.1862A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001136131.3:c.1700A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204301.2:c.1976A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204302.2:c.1919A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204303.2:c.1751A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001385253.1:c.1862A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_201413.3:c.1973A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_201414.3:c.1805A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: APP-related disorder
Synonyms:: APP-related condition
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004117781	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004117781

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 16, 2022)

germline

clinical testing

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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004117781.1

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

Description

The APP c.2030A>G variant is predicted to result in the amino acid substitution p.His677Arg. In the literature, this variant is also referred to as His6Arg, H6R, or the English Familial Disease Mutation. This variant was reported in a family with two siblings affected with early onset familial Alzheimer’s disease, however the APP variant was only present in one of the siblings (Family 209, Janssen et al. 2003. PubMed ID: 12552037). Functional studies have shown that this variant impacts amyloid β-protein assembly (Hori et al. 2006. PubMed ID: 17170111; Ono et al. 2010. PubMed ID: 20452980; Viet et al. 2014. PubMed ID: 24949887). Additional studies suggest that this variant does not alter protein function (Lin et al. 2014. PubMed ID: 25053581). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-27269919-T-C) and is reported as likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/98235/). However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

#	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: Jun 23, 2024

ClinVar

Relating variation to medicine