The PPOX:c.767C>G p.(Pro256Arg) variant has a gnomAD v2.1.1 FAF of 0.9288% (European non-Finnish). In a control population, allele frequency was 5%, with ~10% in the French cohort (Whatley et al 1999, PMID 10486317). In vitro functional studies found normal PPOX activity in transfected COS cells (Kauppinen et al 2001, PMID 11286631). in silico modelling predicts non-deleterious effect (REVEL score 0.495). Fulfils ACMG/AMP criteria BA1, BS3_supporting, BP4 and so is classified as Benign.
ClinVar Genomic variation as it relates to human health
NM_001122764.3(PPOX):c.767C>G (p.Pro256Arg)
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.
Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(4); Likely benign(1)
Uncertain significance(1); Benign(4); Likely benign(1)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001122764.3(PPOX):c.767C>G (p.Pro256Arg)
Variation ID: 8704 Accession: VCV000008704.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q23.3 1: 161169143 (GRCh38) [ NCBI UCSC ] 1: 161138933 (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 Apr 21, 2017 Oct 20, 2024 Jan 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001122764.3:c.767C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001116236.1:p.Pro256Arg missense NM_000309.4:c.767C>G NM_000309.5:c.767C>G NP_000300.1:p.Pro256Arg missense NM_001350128.2:c.668C>G NP_001337057.1:p.Pro223Arg missense NM_001350129.2:c.359C>G NP_001337058.1:p.Pro120Arg missense NM_001350130.2:c.281C>G NP_001337059.1:p.Pro94Arg missense NM_001350131.2:c.281C>G NP_001337060.1:p.Pro94Arg missense NM_001365398.1:c.767C>G NP_001352327.1:p.Pro256Arg missense NM_001365399.1:c.767C>G NP_001352328.1:p.Pro256Arg missense NM_001365400.1:c.359C>G NP_001352329.1:p.Pro120Arg missense NM_001365401.1:c.281C>G NP_001352330.1:p.Pro94Arg missense NC_000001.11:g.161169143C>G NC_000001.10:g.161138933C>G NG_012877.2:g.7753C>G LRG_1078:g.7753C>G LRG_1078t1:c.767C>G LRG_1078p1:p.Pro256Arg P50336:p.Pro256Arg - Protein change
- P256R, P120R, P223R, P94R
- Other names
- -
- Canonical SPDI
- NC_000001.11:161169142:C:G
-
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.
-
0.00280 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00280
1000 Genomes Project 30x 0.00297
Trans-Omics for Precision Medicine (TOPMed) 0.00573
The Genome Aggregation Database (gnomAD) 0.00660
- 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. |
|||
| PPOX | - | - |
GRCh38 GRCh37 |
239 | 278 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jun 30, 2022 | RCV000986448.18 | |
| Benign (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2024 | RCV000961007.30 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 2001 | RCV003324496.4 | |
|
PPOX-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
May 19, 2020 | RCV003924820.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Variegate porphyria
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001135454.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
|
|
Benign
(Jun 30, 2022)
|
criteria provided, single submitter
Method: curation
|
Variegate porphyria
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
unknown
|
Department of Medical Genomics, Royal Prince Alfred Hospital
Accession: SCV002538984.1
First in ClinVar: Jul 08, 2022 Last updated: Jul 08, 2022 |
Comment:
The PPOX:c.767C>G p.(Pro256Arg) variant has a gnomAD v2.1.1 FAF of 0.9288% (European non-Finnish). In a control population, allele frequency was 5%, with ~10% in the … (more)
The PPOX:c.767C>G p.(Pro256Arg) variant has a gnomAD v2.1.1 FAF of 0.9288% (European non-Finnish). In a control population, allele frequency was 5%, with ~10% in the French cohort (Whatley et al 1999, PMID 10486317). In vitro functional studies found normal PPOX activity in transfected COS cells (Kauppinen et al 2001, PMID 11286631). in silico modelling predicts non-deleterious effect (REVEL score 0.495). Fulfils ACMG/AMP criteria BA1, BS3_supporting, BP4 and so is classified as Benign. (less)
Clinical Features:
Increased urinary porphobilinogen (absent) , Abnormal circulating porphyrin concentration (absent)
Indication for testing: Incidental finding
Age: 50-59 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Australia
Comment on evidence:
Patient had direct to consumer DNA testing, then report from Promethease stating she was a Variegate Porphyria carrier (Note that there is a Clinvar Pathogenic … (more)
Patient had direct to consumer DNA testing, then report from Promethease stating she was a Variegate Porphyria carrier (Note that there is a Clinvar Pathogenic classification from OMIM that is incorrect). No clinical or biochemical evidence of VP. (less)
|
|
|
Benign
(May 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Variegate porphyria
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556729.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Variegate porphyria
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001255186.1
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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Benign
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001108036.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004009898.12
First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024 |
Comment:
PPOX: BP4, BS1, BS2
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Apr 01, 2001)
|
no assertion criteria provided
Method: literature only
|
VARIEGATE PORPHYRIA, CHILDHOOD-ONSET
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029459.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 23, 2023 |
Comment on evidence:
For discussion of the c.767C-G transition in exon 7 of the PPOX gene, resulting in a pro256-to-arg (P256R) substitution, that was found in compound heterozygous … (more)
For discussion of the c.767C-G transition in exon 7 of the PPOX gene, resulting in a pro256-to-arg (P256R) substitution, that was found in compound heterozygous state in affected members of 2 Finnish families with childhood-onset variegate porphyria (VPCO; 620483) by Kauppinen et al. (2001), see 600923.0012. (less)
|
|
|
Likely benign
(May 19, 2020)
|
no assertion criteria provided
Method: clinical testing
|
PPOX-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004746364.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
|
Benign
(Jan 06, 2020)
|
no assertion criteria provided
Method: curation
|
Porphyria variegata
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142311.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000309.3:c.767C>G in the PPOX gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database, including eight homozygous occurrences. Functional studies … (more)
NM_000309.3:c.767C>G in the PPOX gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database, including eight homozygous occurrences. Functional studies indicated that this variant resulted in less than half of the normal PPOX activity in the prokaryotic expression system but the activity was almost normal in eukaryotic expression (PMID: 11286631). In addition, Whatley et al. reported this variant as a polymorphism (PMID: 10486317). Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1; BS2; BS3. (less)
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924864.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963218.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
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Comment:
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, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
PPOX: BP4, BS1, BS2
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Comment:
NM_000309.3:c.767C>G in the PPOX gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database, including eight homozygous occurrences. Functional studies indicated that this variant resulted in less than half of the normal PPOX activity in the prokaryotic expression system but the activity was almost normal in eukaryotic expression (PMID: 11286631). In addition, Whatley et al. reported this variant as a polymorphism (PMID: 10486317). Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1; BS2; BS3.
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:
The PPOX:c.767C>G p.(Pro256Arg) variant has a gnomAD v2.1.1 FAF of 0.9288% (European non-Finnish). In a control population, allele frequency was 5%, with ~10% in the French cohort (Whatley et al 1999, PMID 10486317). In vitro functional studies found normal PPOX activity in transfected COS cells (Kauppinen et al 2001, PMID 11286631). in silico modelling predicts non-deleterious effect (REVEL score 0.495). Fulfils ACMG/AMP criteria BA1, BS3_supporting, BP4 and so is classified as Benign.
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, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
PPOX: BP4, BS1, BS2
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Comment:
NM_000309.3:c.767C>G in the PPOX gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database, including eight homozygous occurrences. Functional studies indicated that this variant resulted in less than half of the normal PPOX activity in the prokaryotic expression system but the activity was almost normal in eukaryotic expression (PMID: 11286631). In addition, Whatley et al. reported this variant as a polymorphism (PMID: 10486317). Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1; BS2; BS3.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect. | Kauppinen R | The Journal of investigative dermatology | 2001 | PMID: 11286631 |
| Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. | Whatley SD | American journal of human genetics | 1999 | PMID: 10486317 |
Text-mined citations for rs12735723 ...
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 Nov 25, 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.