ClinVar Miner

Submissions for variant NM_000941.3(POR):c.683C>T (p.Pro228Leu) (rs17853284)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000501875 SCV000596546 uncertain significance not specified 2016-09-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282487 SCV000604908 uncertain significance none provided 2020-02-12 criteria provided, single submitter clinical testing The POR c.683C>T; p.Pro228Leu variant (rs17853284), which is part of the POR*36 allele (Gomes 2009), has been reported to have 40 to 100 percent P450 oxidoreductase activity in assays on CYP2C19, CYP17A1, NADPH Ox, Cyt c Red, CYP17A1, CYP3A4 and HO-1 enzymes (Agrawl 2008, Huang 2005, Marohnic 2001, Moutinho 2012, Pandey 2010), and 20 percent activity on CYP1A2 (Agrawal 2008). The p.Pro228Leu variant is listed in ClinVar (Variation ID: 436385), and is found in the general population with an overall allele frequency of 0.25% (689/277308 alleles, including a single homozygote) in the Genome Aggregation Database. The proline at position 228 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Although the functional assays suggest that the p.Pro228Leu may be a benign polymorphism, there is insufficient information to determine its clinical significance with certainty. References: Agrawal V et al. Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenet Genomics. 2008; 18(7):569-76. Gomes A et al. Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation. Pharmacogenomics. 2009; 10(4):579-99. Huang N et al. Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet. 2005; 76(5):729-49. Marohnic C et al. Mutations of human cytochrome P450 reductase differentially modulate heme oxygenase-1 activity and oligomerization. Arch Biochem Biophys. 2011;513(1):42-50. Moutinho D et al. Altered human CYP3A4 activity caused by Antley-Bixler syndrome-related variants of NADPH-cytochrome P450 oxidoreductase measured in a robust in vitro system. Drug Metab Dispos. 2012; 40(4):754-60. Pandey A et al. Altered heme catabolism by heme oxygenase-1 caused by mutations in human NADPH cytochrome P450 reductase. Biochem Biophys Res Commun. 2010; 400(3):374-8.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000501875 SCV000854986 likely benign not specified 2017-11-28 criteria provided, single submitter clinical testing
Invitae RCV000755371 SCV001021777 likely benign Disordered steroidogenesis due to cytochrome p450 oxidoreductase deficiency 2020-12-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000755371 SCV001320888 uncertain significance Disordered steroidogenesis due to cytochrome p450 oxidoreductase deficiency 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx RCV001584216 SCV001818062 likely benign not provided 2021-06-02 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26582918, 16467261, 27032764, 27068427, 27496950, 21084761, 22462747, 20732302, 21741353, 18551037, 20981092, 17635179, 22252407, 30496128)

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