ClinVar Genomic variation as it relates to human health
NM_018129.4(PNPO):c.673C>T (p.Arg225Cys)
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
-
NM_018129.4(PNPO):c.673C>T (p.Arg225Cys)
Variation ID: 206450 Accession: VCV000206450.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.32 17: 47946669 (GRCh38) [ NCBI UCSC ] 17: 46024035 (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 29, 2016 Oct 20, 2024 Feb 6, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_018129.4:c.673C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060599.1:p.Arg225Cys missense NC_000017.11:g.47946669C>T NC_000017.10:g.46024035C>T NG_008744.1:g.10147C>T - Protein change
- R225C
- Other names
-
p.R225C:CGC>TGC
- Canonical SPDI
- NC_000017.11:47946668:C:T
-
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) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- 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. |
|||
PNPO | - | - |
GRCh38 GRCh37 |
374 | 385 |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 8, 2022 | RCV000188498.29 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV000850584.11 | |
PNPO-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
May 26, 2023 | RCV004537581.1 |
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
(Jul 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000242112.17
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies of in vitro enzyme activity in protein lysates transfected from HeLa cells, demonstrate that R225C drastically reduces enzyme activity to 9% of … (more)
Published functional studies of in vitro enzyme activity in protein lysates transfected from HeLa cells, demonstrate that R225C drastically reduces enzyme activity to 9% of wild type activity (Mills PB et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21292558, 29655203, 31216405, 30671974, 34177756, 24645144, 29610166) (less)
|
|
Pathogenic
(Aug 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pyridoxal phosphate-responsive seizures
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001209920.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs769266169, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral … (more)
This variant is present in population databases (rs769266169, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 225 of the PNPO protein (p.Arg225Cys). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 21292558, 24645144, 25762494). ClinVar contains an entry for this variant (Variation ID: 206450). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg225 amino acid residue in PNPO. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22858719, 24266778, 24645144, 24658933). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PNPO function (PMID: 24645144). 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 PNPO protein function. (less)
|
|
Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pyridoxal phosphate-responsive seizures
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000992806.2
First in ClinVar: Sep 21, 2019 Last updated: Jun 09, 2024 |
|
|
Pathogenic
(May 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pyridoxal phosphate-responsive seizures
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547507.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: PNPO c.673C>T (p.Arg225Cys) results in a non-conservative amino acid change located in the Pyridoxine 5'-phosphate oxidase, dimerisation, C-terminal domain (IPR019576) of the encoded … (more)
Variant summary: PNPO c.673C>T (p.Arg225Cys) results in a non-conservative amino acid change located in the Pyridoxine 5'-phosphate oxidase, dimerisation, C-terminal domain (IPR019576) 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 2.4e-05 in 251418 control chromosomes. c.673C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Pyridoxal 5'-Phosphate-Dependent Epilepsy (example, Veerapandiyan_2011, Mills_2014, Borst_2018, Barile_2020, Jaxybayeva_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Mills_2014). The most pronounced variant effect results in 9% of normal PLP synthesis activity in vitro. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(May 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PNPO-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004117918.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PNPO c.673C>T variant is predicted to result in the amino acid substitution p.Arg225Cys. This variant has been reported in the homozygous state in several … (more)
The PNPO c.673C>T variant is predicted to result in the amino acid substitution p.Arg225Cys. This variant has been reported in the homozygous state in several individuals with pyridoxamine-responsive epilepsy (Veerapandiyan et al 2011. PubMed ID: 21292558; Liu P et al 2019. PubMed ID: 31216405; Jaxybayeva A et al 2021. PubMed ID: 34177756; Borst AJ et al 2018. PubMed ID: 29610166). In vitro experimental studies suggest this variant impacts protein function (Mills et al 2014. PubMed ID: 24645144). Different missense variants affecting the same amino acid (p.Arg225His, p.Arg225Leu) have also been reported in individuals with pyridoxamine 5'-phosphate oxidase deficiency (see, for example, Plecko et al. 2014. PubMed ID: 24658933; Sund et al. 2013. PubMed ID: 22858719). The c.673C>T (p.Arg225Cys) variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-46024035-C-T). This variant is interpreted as pathogenic. (less)
|
|
Likely Pathogenic
(Oct 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pyridoxal phosphate-responsive seizures
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847332.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg225Cys variant in PNPO has been identified in the compound heterozygous state at least 1 individual and in the homozygous state in at least … (more)
The p.Arg225Cys variant in PNPO has been identified in the compound heterozygous state at least 1 individual and in the homozygous state in at least 3 individuals with seizures that were responsive to pyridoxine/pyridoxal 5'-phosphate (Veerapandiyan 2011 PMID: 21292558, Mills 2014 PMID: 24645144, Borst 2018 PMID: 29610166, Barile 2020 PMID: 32788630, Jaxybayeva 2021 PMID: 34177756). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 206450). It was absent from large population studies (gnomAD v.3.1.2). In vitro functional studies from cells transfected with the variant show a drastic reduction in PLP enzyme activity (only 9% activity compared to wild type; Mills 2014 PMID: 24645144). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Another variant involving this codon (p.Arg225His) has been identified in individuals with seizures and is reported as pathogenic by multiple clinical laboratories. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive pyridoxal phosphate-responsive seizures. ACMG/AMP Criteria applied: PM3, PM5, PM2_Supporting, PP3, PS3_Supporting. (less)
|
|
Pathogenic
(Sep 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500132.23
First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
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 |
---|---|---|---|---|
Genomic Investigation of Infantile and Childhood Epileptic Encephalopathies in Kazakhstan: An Urgent Priority. | Jaxybayeva A | Frontiers in neurology | 2021 | PMID: 34177756 |
Molecular characterization of pyridoxine 5'-phosphate oxidase and its pathogenic forms associated with neonatal epileptic encephalopathy. | Barile A | Scientific reports | 2020 | PMID: 32788630 |
B(6) and Bleeding: A Case Report of a Novel Vitamin Toxicity. | Borst AJ | Pediatrics | 2018 | PMID: 29610166 |
Normal Cerebrospinal Fluid Pyridoxal 5'-Phosphate Level in a PNPO-Deficient Patient with Neonatal-Onset Epileptic Encephalopathy. | Levtova A | JIMD reports | 2015 | PMID: 25762494 |
Pyridoxine responsiveness in novel mutations of the PNPO gene. | Plecko B | Neurology | 2014 | PMID: 24658933 |
Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. | Mills PB | Brain : a journal of neurology | 2014 | PMID: 24645144 |
Typical and atypical phenotypes of PNPO deficiency with elevated CSF and plasma pyridoxamine on treatment. | Ware TL | Developmental medicine and child neurology | 2014 | PMID: 24266778 |
Regions of homozygosity identified by SNP microarray analysis aid in the diagnosis of autosomal recessive disease and incidentally detect parental blood relationships. | Sund KL | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22858719 |
Electroencephalographic and seizure manifestations of pyridoxal 5'-phosphate-dependent epilepsy. | Veerapandiyan A | Epilepsy & behavior : E&B | 2011 | PMID: 21292558 |
Text-mined citations for rs769266169 ...
HelpRecord last updated Nov 03, 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.