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 alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (66 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated FAD-binding FR-type domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and has been observed in many homozygous and compound heterozygous patients with P450 oxidoreductase deficiency. It is regarded as the most common variant in Caucasian populations, and results in a mild-moderate form of disease (ClinVar, PMID: 27068427, PMID: 22162478). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays have demonstrated that this variant causes significant reductions in enzyme activity and steroid biosynthesis (PMID: 27068427). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ClinVar Genomic variation as it relates to human health
NM_001395413.1(POR):c.850G>C (p.Ala284Pro)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(11)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001395413.1(POR):c.850G>C (p.Ala284Pro)
Variation ID: 16902 Accession: VCV000016902.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q11.23 7: 75983548 (GRCh38) [ NCBI UCSC ] 7: 75612866 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 9, 2015 Oct 8, 2024 Jan 7, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001395413.1:c.850G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001382342.1:p.Ala284Pro missense NM_000941.3:c.859G>C NM_001367562.3:c.850G>C NP_001354491.2:p.Ala284Pro missense NM_001382655.3:c.904G>C NP_001369584.2:p.Ala302Pro missense NM_001382657.2:c.850G>C NP_001369586.2:p.Ala284Pro missense NM_001382658.3:c.850G>C NP_001369587.2:p.Ala284Pro missense NM_001382659.3:c.850G>C NP_001369588.2:p.Ala284Pro missense NM_001382662.3:c.850G>C NP_001369591.2:p.Ala284Pro missense NC_000007.14:g.75983548G>C NC_000007.13:g.75612866G>C NG_008930.1:g.73447G>C NG_084576.1:g.880G>C - Protein change
- A302P
- Other names
-
A287P
A284P
- Canonical SPDI
- NC_000007.14:75983547:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00022
The Genome Aggregation Database (gnomAD) 0.00023
The Genome Aggregation Database (gnomAD), exomes 0.00024
Trans-Omics for Precision Medicine (TOPMed) 0.00027
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00032
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LOC126860075 | - | - | - | GRCh38 | - | 97 |
| POR | - | - |
GRCh38 GRCh37 |
720 | 862 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Jan 12, 2023 | RCV000018401.32 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 7, 2024 | RCV000170457.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 21, 2022 | RCV000519572.9 | |
|
POR-related disorder
|
Pathogenic (2) |
criteria provided, single submitter
|
Feb 1, 2022 | RCV002243651.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
POR-related disorder
Affected status: yes
Allele origin:
biparental
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV002515366.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768871.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (66 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated FAD-binding FR-type domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and has been observed in many homozygous and compound heterozygous patients with P450 oxidoreductase deficiency. It is regarded as the most common variant in Caucasian populations, and results in a mild-moderate form of disease (ClinVar, PMID: 27068427, PMID: 22162478). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays have demonstrated that this variant causes significant reductions in enzyme activity and steroid biosynthesis (PMID: 27068427). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Jan 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807528.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Number of individuals with the variant: 1
Clinical Features:
Neonatal asphyxia (present) , Long second metacarpal (present) , Primary Caesarian section (present) , Fused lips (present) , Abnormal delivery (present) , Caesarian section (present) … (more)
Neonatal asphyxia (present) , Long second metacarpal (present) , Primary Caesarian section (present) , Fused lips (present) , Abnormal delivery (present) , Caesarian section (present) , Long toe (present) , Depressed nasal bridge (present) , Proximal placement of thumb (present) , Neonatal respiratory distress (present) , Proptosis (present) , Frontal bossing (present) , Low hanging columella (present) , Brachycephaly (present) , Low-set, posteriorly rotated ears (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(Nov 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000616830.5
First in ClinVar: Dec 19, 2017 Last updated: Mar 26, 2023 |
Comment:
Published functional studies demonstrate a decreased rate of flavin reduction and conformational protein instability leading to proteolytic susceptibility (Jin et al., 2015; McCammon et al., … (more)
Published functional studies demonstrate a decreased rate of flavin reduction and conformational protein instability leading to proteolytic susceptibility (Jin et al., 2015; McCammon et al., 2016); 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, 22252407, 19621255, 15793702, 17389698, 19837910, 17505056, 17635179, 16495354, 17062779, 25728647, 18551037, 20697309, 20940534, 22547083, 22719896, 14758361, 26969897, 26670660, 27496950, 18259105, 12116245, 15220035, 31230720, 31837199, 31980526, 32242900, 34426522, 31589614, 31128914, 35842891, 22162478, 21190981) (less)
|
|
|
Pathogenic
(Oct 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019499.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002195313.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 287 of the POR protein (p.Ala287Pro). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 287 of the POR protein (p.Ala287Pro). This variant is present in population databases (rs121912974, gnomAD 0.05%). This missense change has been observed in individuals with POR deficiency (PMID: 14758361, 22162478). ClinVar contains an entry for this variant (Variation ID: 16902). 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: 14758361, 18551037, 20940534, 21741353). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 01, 2005)
|
no assertion criteria provided
Method: literature only
|
ANTLEY-BIXLER SYNDROME WITH GENITAL ANOMALIES AND DISORDERED STEROIDOGENESIS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038683.3
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2015 |
Comment on evidence:
In a child with bony features of Antley-Bixler syndrome with genital ambiguity and abnormal steroidogenesis (ABS1; 201750), Fluck et al. (2004) found apparent homozygosity for … (more)
In a child with bony features of Antley-Bixler syndrome with genital ambiguity and abnormal steroidogenesis (ABS1; 201750), Fluck et al. (2004) found apparent homozygosity for a nucleotide substitution 859G-C in the POR gene leading to an ala287-to-pro (A287P) substitution. This child had been described by Kelley et al. (2002). The mother was heterozygous for the mutation; paternal DNA was not available. Huang et al. (2005) sequenced the POR gene in 29 individuals with Antley-Bixler syndrome and/or hormonal findings that suggested POR deficiency. Fifteen patients carried POR mutations on both alleles; 4 carried mutations on only 1 allele. The 34 affected POR alleles included 10 with A287P, all in Caucasians. For discussion of the A287P mutation in the POR gene that was found in compound heterozygous state in a patient with congenital adrenal hyperplasia due to apparent combined deficiency of P450C17 and P450C21 (613571) by Arlt et al. (2004), see 124015.0005. (less)
|
|
|
Pathogenic
(May 01, 2005)
|
no assertion criteria provided
Method: literature only
|
DISORDERED STEROIDOGENESIS DUE TO CYTOCHROME P450 OXIDOREDUCTASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000222889.1
First in ClinVar: May 09, 2015 Last updated: May 09, 2015 |
Comment on evidence:
In a child with bony features of Antley-Bixler syndrome with genital ambiguity and abnormal steroidogenesis (ABS1; 201750), Fluck et al. (2004) found apparent homozygosity for … (more)
In a child with bony features of Antley-Bixler syndrome with genital ambiguity and abnormal steroidogenesis (ABS1; 201750), Fluck et al. (2004) found apparent homozygosity for a nucleotide substitution 859G-C in the POR gene leading to an ala287-to-pro (A287P) substitution. This child had been described by Kelley et al. (2002). The mother was heterozygous for the mutation; paternal DNA was not available. Huang et al. (2005) sequenced the POR gene in 29 individuals with Antley-Bixler syndrome and/or hormonal findings that suggested POR deficiency. Fifteen patients carried POR mutations on both alleles; 4 carried mutations on only 1 allele. The 34 affected POR alleles included 10 with A287P, all in Caucasians. For discussion of the A287P mutation in the POR gene that was found in compound heterozygous state in a patient with congenital adrenal hyperplasia due to apparent combined deficiency of P450C17 and P450C21 (613571) by Arlt et al. (2004), see 124015.0005. (less)
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: research
|
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis
This variant was identified in an
(more...)
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV001167495.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Number of individuals with the variant: 3
Family history: yes
|
|
|
Pathogenic
(Aug 12, 2024)
|
no assertion criteria provided
Method: clinical testing
|
POR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005360107.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The POR c.859G>C variant is predicted to result in the amino acid substitution p.Ala287Pro. This variant has been reported to be the most common pathogenic … (more)
The POR c.859G>C variant is predicted to result in the amino acid substitution p.Ala287Pro. This variant has been reported to be the most common pathogenic POR variant found in patients of European ancestry with P450 oxidoreductase deficiency (see for example, Fluck et al. 2004. PubMed ID: 14758361; Krone et al. 2012. PubMed ID: 22162478). This variant is reported in 0.05% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV002011801.2
First in ClinVar: Nov 06, 2021 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Comment:
Published functional studies demonstrate a decreased rate of flavin reduction and conformational protein instability leading to proteolytic susceptibility (Jin et al., 2015; McCammon et al., 2016); 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, 22252407, 19621255, 15793702, 17389698, 19837910, 17505056, 17635179, 16495354, 17062779, 25728647, 18551037, 20697309, 20940534, 22547083, 22719896, 14758361, 26969897, 26670660, 27496950, 18259105, 12116245, 15220035, 31230720, 31837199, 31980526, 32242900, 34426522, 31589614, 31128914, 35842891, 22162478, 21190981)
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 287 of the POR protein (p.Ala287Pro). This variant is present in population databases (rs121912974, gnomAD 0.05%). This missense change has been observed in individuals with POR deficiency (PMID: 14758361, 22162478). ClinVar contains an entry for this variant (Variation ID: 16902). 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: 14758361, 18551037, 20940534, 21741353). For these reasons, this variant has been classified as Pathogenic.
Comment on condition
This variant was identified in an individual with arthrogryposis and multiple system disorder
Comment:
The POR c.859G>C variant is predicted to result in the amino acid substitution p.Ala287Pro. This variant has been reported to be the most common pathogenic POR variant found in patients of European ancestry with P450 oxidoreductase deficiency (see for example, Fluck et al. 2004. PubMed ID: 14758361; Krone et al. 2012. PubMed ID: 22162478). This variant is reported in 0.05% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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 alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (66 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated FAD-binding FR-type domain (Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and has been observed in many homozygous and compound heterozygous patients with P450 oxidoreductase deficiency. It is regarded as the most common variant in Caucasian populations, and results in a mild-moderate form of disease (ClinVar, PMID: 27068427, PMID: 22162478). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays have demonstrated that this variant causes significant reductions in enzyme activity and steroid biosynthesis (PMID: 27068427). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Comment:
Published functional studies demonstrate a decreased rate of flavin reduction and conformational protein instability leading to proteolytic susceptibility (Jin et al., 2015; McCammon et al., 2016); 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, 22252407, 19621255, 15793702, 17389698, 19837910, 17505056, 17635179, 16495354, 17062779, 25728647, 18551037, 20697309, 20940534, 22547083, 22719896, 14758361, 26969897, 26670660, 27496950, 18259105, 12116245, 15220035, 31230720, 31837199, 31980526, 32242900, 34426522, 31589614, 31128914, 35842891, 22162478, 21190981)
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 287 of the POR protein (p.Ala287Pro). This variant is present in population databases (rs121912974, gnomAD 0.05%). This missense change has been observed in individuals with POR deficiency (PMID: 14758361, 22162478). ClinVar contains an entry for this variant (Variation ID: 16902). 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: 14758361, 18551037, 20940534, 21741353). For these reasons, this variant has been classified as Pathogenic.
Comment on condition
This variant was identified in an individual with arthrogryposis and multiple system disorder
Comment:
The POR c.859G>C variant is predicted to result in the amino acid substitution p.Ala287Pro. This variant has been reported to be the most common pathogenic POR variant found in patients of European ancestry with P450 oxidoreductase deficiency (see for example, Fluck et al. 2004. PubMed ID: 14758361; Krone et al. 2012. PubMed ID: 22162478). This variant is reported in 0.05% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations. | Belanger Deloge R | European journal of human genetics : EJHG | 2023 | PMID: 36474027 |
| P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms. | Burkhard FZ | The Journal of steroid biochemistry and molecular biology | 2017 | PMID: 27068427 |
| Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. | Krone N | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22162478 |
| Mutations of human cytochrome P450 reductase differentially modulate heme oxygenase-1 activity and oligomerization. | Marohnic CC | Archives of biochemistry and biophysics | 2011 | PMID: 21741353 |
| Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro. | Sandee D | Pharmacogenetics and genomics | 2010 | PMID: 20940534 |
| Restoration of mutant cytochrome P450 reductase activity by external flavin. | Nicolo C | Molecular and cellular endocrinology | 2010 | PMID: 20188793 |
| Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. | Agrawal V | Pharmacogenetics and genomics | 2008 | PMID: 18551037 |
| Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. | Huang N | American journal of human genetics | 2005 | PMID: 15793702 |
| Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. | Arlt W | Lancet (London, England) | 2004 | PMID: 15220035 |
| Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. | Flück CE | Nature genetics | 2004 | PMID: 14758361 |
| Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia. | Kelley RI | American journal of medical genetics | 2002 | PMID: 12116245 |
| click to load more click to collapse | ||||
Text-mined citations for rs121912974 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.