Submissions for variant NM_001395413.1(POR):c.674C>T (p.Pro225Leu)

gnomAD frequency: 0.00271  dbSNP: rs17853284

Total submissions: 8

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	RCV001584216	SCV000604908	uncertain significance	not provided	2023-10-26	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.
Eurofins Ntd Llc (ga)	RCV000501875	SCV000854986	likely benign	not specified	2017-11-28	criteria provided, single submitter	clinical testing
Invitae	RCV000755371	SCV001021777	likely benign	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000755371	SCV001320888	uncertain significance	Congenital adrenal hyperplasia 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)
Revvity Omics, Revvity	RCV001584216	SCV003809803	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535610	SCV004747104	likely benign	POR-related disorder	2019-04-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).