NM_000041.2(APOE):c.526C>T (p.Arg176Cys) AND not provided

Germline classification:: Likely benign; other; risk factor (5 submissions)
Last evaluated:: Aug 1, 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:: RCV000346955.21

Allele description [Variation Report for NM_000041.2(APOE):c.526C>T (p.Arg176Cys)]

NM_000041.2(APOE):c.526C>T (p.Arg176Cys)

Gene:

APOE:apolipoprotein E [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.32

Genomic location:

Preferred name:

NM_000041.2(APOE):c.526C>T (p.Arg176Cys)

Other names:

R158C; R148C

HGVS:

NC_000019.10:g.44908822C>T
NG_007084.2:g.8041C>T
NM_000041.4:c.526C>TMANE SELECT
NM_001302688.2:c.604C>T
NM_001302689.2:c.526C>T
NM_001302690.2:c.526C>T
NM_001302691.2:c.526C>T
NP_000032.1:p.Arg176Cys
NP_001289617.1:p.Arg202Cys
NP_001289618.1:p.Arg176Cys
NP_001289619.1:p.Arg176Cys
NP_001289620.1:p.Arg176Cys
NC_000019.9:g.45412079C>T
NM_000041.2:c.526C>T
NM_000041.3:c.526C>T
P02649:p.Arg176Cys

Protein change:

R176C; ARG148CYS

Links:

PharmGKB: 1183492249; PharmGKB: 1183492249PA448500; PharmGKB Clinical Annotation: 1183492249; UniProtKB: P02649#VAR_000664; OMIM: 107741.0001; OMIM: 107741.0009; OMIM: 107741.0019; OMIM: 107741.0021; dbSNP: rs7412

NCBI 1000 Genomes Browser:

rs7412

Molecular consequence:

NM_000041.4:c.526C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001302688.2:c.604C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001302689.2:c.526C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001302690.2:c.526C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001302691.2:c.526C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000333416	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	other (Feb 11, 2016)	germline	clinical testing	Citation Link,
SCV000987597	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	risk factor	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001550093	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV001926324	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV004033681	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Aug 1, 2023)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	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 Eurofins Ntd Llc (ga), SCV000333416.3

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

#	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		1	not provided	not provided	not provided

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000987597.1

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

#	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		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001550093.1

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

Description

The APOE p.Arg176Cys variant, also known as the APOE Å’Âµ2 allele, was identified in dbSNP (ID: rs7412), ClinVar (reported by EGL Genetics in relation to drug metabolism), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 10996 of 168078 chromosomes (465 homozygous) at a frequency of 0.065422 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1632 of 15264 chromosomes (freq: 0.1069), Ashkenazi Jewish in 664 of 8410 chromosomes (freq: 0.07895), European (non-Finnish) in 5202 of 67810 chromosomes (freq: 0.07671), East Asian in 947 of 12608 chromosomes (freq: 0.07511), Other in 328 of 5174 chromosomes (freq: 0.06339), European (Finnish) in 472 of 10686 chromosomes (freq: 0.04417), South Asian in 947 of 22604 chromosomes (freq: 0.0419), and Latino in 804 of 25522 chromosomes (freq: 0.0315). Homozygous individuals with the APOE Å’Âµ2 genotype are at a higher risk of developing type III hyperlipoproteinemia and mouse models with the APOE Å’Âµ2 genotype develop a clear type III hyperlipoproteinemia phenotype (Breslow_1982_PMID: 7175379; Sullivan_1998_PMID: 9649566). However, this variant does not show full penetrance for type III hyperlipoproteinemia and other variants in conjunction with the APOE Å’Âµ2 genotype have been suggested to contribute to the phenotype (Sakuma_2014_PMID: 24953047). Another study found that carriers of the APOE Å’Âµ2 allele had lower baseline LDL cholesterol levels as well as a greater reduction of LDL-C from atorvastatin and pravastatin treatment compared to APOE Å’Âµ4 carriers, implicating this variant as a pharmacogenetic variant (Meg_2009_PMID: 19667110). The p.Arg176 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001926324.1

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

#	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		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004033681.5

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

Description

APOE: PM5, BS1, BS2

#	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: Apr 20, 2024

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