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

gnomAD frequency: 0.07986  dbSNP: rs7412

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV000211178	SCV000268391	drug response	atorvastatin response - Efficacy	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications.
Eurofins Ntd Llc (ga)	RCV000346955	SCV000333416	other	not provided	2016-02-11	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000346955	SCV000987597	risk factor	not provided		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262472	SCV001440366	benign	Hypercholesterolemia	2019-01-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000346955	SCV004033681	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	APOE: PM5, BS1, BS2
OMIM	RCV000019428	SCV000039717	pathogenic	Familial type 3 hyperlipoproteinemia	2005-10-01	no assertion criteria provided	literature only
Pharmacogenomics Lab, Chungbuk National University	RCV000845582	SCV000889947	drug response	Warfarin response	2010-08-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000346955	SCV001550093	uncertain significance	not provided		no assertion criteria provided	clinical testing	The APOE p.Arg176Cys variant, also known as the APOE ε2 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 ε2 genotype are at a higher risk of developing type III hyperlipoproteinemia and mouse models with the APOE ε2 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 ε2 genotype have been suggested to contribute to the phenotype (Sakuma_2014_PMID: 24953047). Another study found that carriers of the APOE ε2 allele had lower baseline LDL cholesterol levels as well as a greater reduction of LDL-C from atorvastatin and pravastatin treatment compared to APOE ε4 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529800	SCV001743895	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000346955	SCV001926324	likely benign	not provided		no assertion criteria provided	clinical testing