ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 539 of the POR protein (p.Gly539Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of POR-related conditions (PMID: 15793702, 18559916, 31598952, 34009138). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 16915). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects POR function (PMID: 15793702). For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (MIM#201750), and disordered steroidogenesis due to cytochrome P450 oxidoreductase (MIM#613571). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated FAD-binding FR-type domain, and forms part of the structural motif (Uniprot, NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic (LOVD, ClinVar) and has been observed in multiple homozygous patients with P450 oxidoreductase deficiency (PORD) and compound heterozygous patients with Antley-Bixler syndrome or PORD (PMID: 18559916, PMID: 15793702, PMID: 19837910, PMID: 23878291). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays have proven that this variant results in significantly reduced eletron transport and catalytic efficiency (PMID: 22252407). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Variant summary: POR c.1606G>A (p.Gly536Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 177730 control chromosomes (gnomAD). c.1606G>A (also known as c.1615G>A, p.G539R.) has been reported in the literature in multiple bi-allelic individuals affected with Congenital Adrenal Hyperplasia (example: Huang_2005, Hershkovitz_2008, Tenenbaum-Rakover_2021). At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated that this variant impairs normal activity of the protein (example: Huang_2005). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15793702, 18559916, 34009138). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The POR c.1615G>A variant is predicted to result in the amino acid substitution p.Gly539Arg. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with Antley-Bixler syndrome with genital anomalies and P450 Oxidoreductase Deficiency (Sahakitrungruang et al. 2009. PubMed ID: 19837910; Sánchez-Garvín et al. 2013. PubMed ID: 23878291; Peng et al. 2019. PubMed ID: 31598952; Tenenbaum-Rakover et al. 2021. PubMed ID: 34009138). In vitro and biochemical experimental studies suggest this variant impacts protein function (Huang et al. 2005. PubMed ID: 15793702; Moutinho et al. 2012. PubMed ID: 22252407).This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.