ClinVar Miner

Submissions for variant NM_000041.2(APOE):c.526C>T (p.Arg176Cys) (rs7412)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000211178 SCV000268391 drug response atorvastatin response - Efficacy 2016-02-26 reviewed by expert panel curation PharmGKB Level of Evidence 2A: Annotation for a variant-drug combination that qualifies for level 2B where the variant is within a VIP (Very Important Pharmacogene) as defined by PharmGKB. The variants in level 2A are in known pharmacogenes, so functional significance is more likely.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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
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.

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