ClinVar Miner

Submissions for variant NM_001395413.1(POR):c.889G>A (p.Glu297Lys)

gnomAD frequency: 0.00044  dbSNP: rs11540674
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001160551 SCV001322361 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.
Invitae RCV001160551 SCV001717104 benign Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency 2024-01-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222671 SCV002500325 benign not specified 2023-03-16 criteria provided, single submitter clinical testing Variant summary: POR c.889G>A (p.Glu297Lys) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 249048 control chromosomes (gnomAD), predominantly at a frequency of 0.014 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in POR causing Congenital Adrenal Hyperplasia phenotype (0.00091), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. Experimental studies by Agrawal_2008 evaluating the variants impact on protein function has shown that the variant does not impact 17-alpha hydroxylase or 17,20 lyase activity. Nor does it impact Cytochrome C reduction or NADPH oxidation. The variant did induce lower levels of CYP1A2 and CYP2C19 activity in vivo (84% and 81%, respectively), but the authors consider this as within normal limits. Two ClinVar submitters have assessed the variant since 2014: one classified the variant benign, and one classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

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