ClinVar Genomic variation as it relates to human health
NM_000097.7(CPOX):c.1339C>T (p.Arg447Cys)
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.
Likely pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000097.7(CPOX):c.1339C>T (p.Arg447Cys)
Variation ID: 459 Accession: VCV000000459.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q11.2 3: 98580709 (GRCh38) [ NCBI UCSC ] 3: 98299553 (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 Apr 4, 2013 Feb 14, 2024 Jan 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000097.7:c.1339C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000088.3:p.Arg447Cys missense NC_000003.12:g.98580709G>A NC_000003.11:g.98299553G>A NG_015994.2:g.17903C>T LRG_1077:g.17903C>T LRG_1077t1:c.1339C>T LRG_1077p1:p.Arg447Cys P36551:p.Arg447Cys - Protein change
- R447C
- Other names
- -
- Canonical SPDI
- NC_000003.12:98580708: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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00025
Trans-Omics for Precision Medicine (TOPMed) 0.00029
The Genome Aggregation Database (gnomAD), exomes 0.00040
Exome Aggregation Consortium (ExAC) 0.00049
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 | ||
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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
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. |
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CPOX | - | - |
GRCh38 GRCh37 |
187 | 285 |
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
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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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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2002 | RCV000000488.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2021 | RCV000415159.3 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 6, 2024 | RCV001046689.7 |
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. |
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Uncertain significance
(Oct 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary coproporphyria
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761901.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary coproporphyria
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV000328791.2
First in ClinVar: Jan 13, 2017 Last updated: Mar 18, 2023 |
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Likely pathogenic
(Mar 07, 2023)
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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: SCV004034761.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
Comment:
Reported with a second CPOX variant on the same allele (in cis) in affected individuals from three families with hereditary coproporphyria, as well as without … (more)
Reported with a second CPOX variant on the same allele (in cis) in affected individuals from three families with hereditary coproporphyria, as well as without a second CPOX variant in an unaffected individual from one of these families (Wiman et al., 2002); Published functional studies demonstrate significantly reduced CPOX enzyme activity (Lamoril et al., 2001); 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: 11309681, 27959697, 34426522, 31589614, 33763395, 12181641) (less)
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Uncertain significance
(Feb 24, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226139.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PS3
Number of individuals with the variant: 2
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Uncertain significance
(Jan 06, 2024)
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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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Invitae
Accession: SCV001210603.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 447 of the CPOX protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 447 of the CPOX protein (p.Arg447Cys). This variant is present in population databases (rs28931603, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of coproporphyria (PMID: 11309681, 12181641, 27959697, 33763395). ClinVar contains an entry for this variant (Variation ID: 459). 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 not expected to disrupt CPOX protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CPOX function (PMID: 11309681). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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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Pathogenic
(Jan 01, 2002)
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no assertion criteria provided
Method: literature only
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COPROPORPHYRIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020637.2
First in ClinVar: Apr 04, 2013 Last updated: May 31, 2020 |
Comment on evidence:
Lamoril et al. (2001) identified a 1339C-T mutation in exon 7 of the CPO gene, resulting in an arg447-to-cys (R447C) substitution, in association with coproporphyria … (more)
Lamoril et al. (2001) identified a 1339C-T mutation in exon 7 of the CPO gene, resulting in an arg447-to-cys (R447C) substitution, in association with coproporphyria (HCP; 121300). Wiman et al. (2002) found the R447C mutation and the R331W mutation (612732.0001) in exon 5 on the same allele in patients with coproporphyria. (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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Clinical and Genetic Spectra of Inherited Liver Disease in Children in China. | Fang Y | Frontiers in pediatrics | 2021 | PMID: 33763395 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. | Posey JE | The New England journal of medicine | 2017 | PMID: 27959697 |
Identification of an AluY-mediated deletion of exon 5 in the CPOX gene by MLPA analysis in patients with hereditary coproporphyria. | Barbaro M | Clinical genetics | 2012 | PMID: 21231929 |
Two novel mutations and coexistence of the 991C>T and the 1339C>T mutation on a single allele in the coproporphyrinogen oxidase gene in Swedish patients with hereditary coproporphyria. | Wiman A | Journal of human genetics | 2002 | PMID: 12181641 |
Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria. | Lamoril J | American journal of human genetics | 2001 | PMID: 11309681 |
Text-mined citations for rs28931603 ...
HelpRecord last updated Feb 20, 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.