rs72557954
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001395413.1(POR):c.1811A>G(p.Tyr604Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000745 in 1,610,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y604Y) has been classified as Likely benign.
Frequency
Consequence
NM_001395413.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POR | NM_001395413.1 | c.1811A>G | p.Tyr604Cys | missense_variant | 15/16 | ENST00000461988.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POR | ENST00000461988.6 | c.1811A>G | p.Tyr604Cys | missense_variant | 15/16 | 1 | NM_001395413.1 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000110 AC: 27AN: 244454Hom.: 0 AF XY: 0.000113 AC XY: 15AN XY: 133260
GnomAD4 exome AF: 0.0000802 AC: 117AN: 1458306Hom.: 0 Cov.: 34 AF XY: 0.0000800 AC XY: 58AN XY: 725162
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 607 of the POR protein (p.Tyr607Cys). This variant is present in population databases (rs72557954, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of POR-related conditions (PMID: 20410220, 31888681, 33864926). 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: 1254698). 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: 18230729, 18551037, 20410220, 31888681). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2022 | Published functional studies demonstrate this variant impairs cytochrome protein activity (Agrawal et al., 2008; Flck CE and Pandey AV., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27068427, 16915000, 18930113, 18230729, 31128914, 22162478, 31888681, 18551037, Li2020[article], 20410220, 27032764, 24847272, 18493134, 34426522, 27535533) - |
Congenital adrenal hyperplasia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 24, 2023 | Variant summary: POR c.1811A>G/p.Tyr604Cys (legacy name: c.1820A>G) results in a non-conservative amino acid change located in the Oxidoreductase FAD/NAD(P)-binding domain (IPR001433) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 244454 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POR causing Congenital Adrenal Hyperplasia (0.00011 vs 0.00091), allowing no conclusion about variant significance. c.1811A>G has been reported in the literature in biallelic individuals affected with Congenital Adrenal Hyperplasia (e.g. Idkowiak_2010, Wang_2021). These data indicate that the variant may be associated with disease. The variant was experimentally determined to impact the metabolism of several steroid hormones (Agrawal_2008, Idkowiak_2010), with the most pronounced variant effect resulting in <10% of normal activity (Agrawal_2008). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3150099:Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 19, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at