Submissions for variant NM_001395413.1(POR):c.1361G>A (p.Arg454His)

gnomAD frequency: 0.00005  dbSNP: rs28931608

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000018407	SCV000267459	likely pathogenic	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	2016-03-18	criteria provided, single submitter	reference population
Invitae	RCV000018407	SCV000828629	pathogenic	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 457 of the POR protein (p.Arg457His). This variant is present in population databases (rs28931608, gnomAD 0.05%). This missense change has been observed in individuals with POR-related conditions (PMID: 14758361, 15483095, 20124576, 28841001). ClinVar contains an entry for this variant (Variation ID: 16907). 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: 18551037, 20940534, 22252407, 22547083). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490385	SCV002789467	pathogenic	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis; Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis; Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	2022-05-16	criteria provided, single submitter	clinical testing
GeneDx	RCV003150931	SCV004014196	pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect resulting in reduced enzyme activity (Flck et al., 2004); 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: 21741353, 20732302, 20940534, 20124576, 20697309, 32820517, 16495354, 17062779, 22252407, 22123124, 17635179, 22162478, 18551037, 22547083, 21808038, 16470797, 28288674, 16439592, 18853185, 28841001, 29289577, 31299979, 31754721, 33336784, 29944250, 32973886, 35070845, 19258400, 14758361)
OMIM	RCV000018406	SCV000038688	pathogenic	Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis	2006-03-15	no assertion criteria provided	literature only
OMIM	RCV000018407	SCV000038689	pathogenic	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	2006-03-15	no assertion criteria provided	literature only
GeneReviews	RCV000018407	SCV002011802	not provided	Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency		no assertion provided	literature only
Genetic Services Laboratory, University of Chicago	RCV003150931	SCV003839908	pathogenic	not provided	2022-08-15	no assertion criteria provided	clinical testing	This sequence change, c.1370G>A, is in exon 12 results and in an amino acid change, p.Arg457His. The p.Arg457His change affects a highly conserved amino acid residue located in a domain of the POR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, Align GVGD, REVEL) provide contradictory results for the p.Arg457His substitution. This sequence change has previously been described in several patients with cytochrome P450 oxidoreductase deficiency (POR) deficiency with or without Antley-Bixler syndrome and is considered a founder mutation in the Japanese population (PMID: 15483095, 16470797, 14758361, 19258400). This sequence change has been described in the gnomAD database with a frequency of 0.05% in the East Asian subpopulation (dbSNP rs28931608). These collective evidences indicate that this sequence change is pathogenic.