ClinVar Genomic variation as it relates to human health
NM_001395413.1(POR):c.1208G>A (p.Arg403His)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001395413.1(POR):c.1208G>A (p.Arg403His)
Variation ID: 911635 Accession: VCV000911635.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.23 7: 75984927 (GRCh38) [ NCBI UCSC ] 7: 75614245 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 31, 2020 Feb 7, 2023 Aug 22, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001395413.1:c.1208G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001382342.1:p.Arg403His missense NM_001367562.3:c.1208G>A NP_001354491.2:p.Arg403His missense NM_001382655.3:c.1262G>A NP_001369584.2:p.Arg421His missense NM_001382657.2:c.1208G>A NP_001369586.2:p.Arg403His missense NM_001382658.3:c.1208G>A NP_001369587.2:p.Arg403His missense NM_001382659.3:c.1208G>A NP_001369588.2:p.Arg403His missense NM_001382662.3:c.1208G>A NP_001369591.2:p.Arg403His missense NC_000007.14:g.75984927G>A NC_000007.13:g.75614245G>A NG_008930.1:g.74826G>A - Protein change
- R403H, R421H
- Other names
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- Canonical SPDI
- NC_000007.14:75984926:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00017
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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POR | - | - |
GRCh38 GRCh37 |
699 | 842 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2022 | RCV001164198.16 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2021 | RCV001546288.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 18, 2022 | RCV002483918.8 |
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
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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
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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
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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. |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001326307.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
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, … (more)
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. (less)
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Uncertain significance
(Mar 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473361.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The POR c.1217G>A; p.Arg406His variant (rs72557929) is reported in the literature in a cohort of healthy individuals (Huang 2008). This variant is found in the … (more)
The POR c.1217G>A; p.Arg406His variant (rs72557929) is reported in the literature in a cohort of healthy individuals (Huang 2008). This variant is found in the non-Finnish European population with an overall allele frequency of 0.02% (23/124870 alleles) in the Genome Aggregation Database. The arginine at codon 406 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Functional analyses suggest the p.Arg406His variant protein supports normal activity of partner proteins but exhibits slightly reduced POR enzymatic activity (Agrawal 2008, Huang 2008), though it is unknown if this slight reduction is clinically significant. Due to limited information, the clinical significance of the p.Arg406His variant is uncertain at this time. References: Agrawal et al. Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenet Genomics. 2008 Jul;18(7):569-76. Huang et al. Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1733-8. (less)
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Uncertain significance
(Jan 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001765784.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not reported as pathogenic or benign in association with a disease … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not reported as pathogenic or benign in association with a disease to our our knowledge. However, identified in a healthy population and functional studies demonstrate a moderate reduction in protein activities in multiple enzymatic assays (Huang et al., 2008; Agrawal et al., 2008); This variant is associated with the following publications: (PMID: 27068427, 25133307, 18433346, 24847272, 23353702, 18930113, 18551037, 18230729) (less)
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Uncertain significance
(Feb 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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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
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002791036.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Aug 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002189204.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 406 of the POR protein (p.Arg406His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 406 of the POR protein (p.Arg406His). This variant is present in population databases (rs72557929, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with POR-related conditions. ClinVar contains an entry for this variant (Variation ID: 911635). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POR function (PMID: 18230729, 18551037). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. | Agrawal V | Pharmacogenetics and genomics | 2008 | PMID: 18551037 |
Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. | Huang N | Proceedings of the National Academy of Sciences of the United States of America | 2008 | PMID: 18230729 |
Text-mined citations for rs72557929 ...
HelpRecord last updated Mar 23, 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.