ClinVar Genomic variation as it relates to human health
NM_018129.4(PNPO):c.148G>A (p.Glu50Lys)
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_018129.4(PNPO):c.148G>A (p.Glu50Lys)
Variation ID: 206440 Accession: VCV000206440.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.32 17: 47943315 (GRCh38) [ NCBI UCSC ] 17: 46020681 (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 29, 2016 Feb 4, 2024 Aug 22, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018129.4:c.148G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060599.1:p.Glu50Lys missense NC_000017.11:g.47943315G>A NC_000017.10:g.46020681G>A NG_008744.1:g.6793G>A Q9NVS9:p.Glu50Lys - Protein change
- E50K
- Other names
- p.E50K:GAG>AAG
- Canonical SPDI
- NC_000017.11:47943314: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00009
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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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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PNPO | - | - |
GRCh38 GRCh37 |
373 | 382 |
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
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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 (1) |
criteria provided, single submitter
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Feb 13, 2017 | RCV000188488.2 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2022 | RCV001042917.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 7, 2022 | RCV002271452.1 |
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
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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
(Feb 13, 2017)
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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: SCV000242102.13
First in ClinVar: Aug 08, 2015 Last updated: May 29, 2016 |
Comment:
p.Glu50Lys (GAG>AAG): c.148 G>A in exon 2 of the PNPO gene (NM_018129.3). The E50K variant was previously reported in an affected patient who was homozygous … (more)
p.Glu50Lys (GAG>AAG): c.148 G>A in exon 2 of the PNPO gene (NM_018129.3). The E50K variant was previously reported in an affected patient who was homozygous for E50K and homozygous for a splice mutation (Mills et al., 2005). Functional analysis demonstrated normal enzyme activity in the presence of the homozygous E50K variant, and therefore the authors concluded that E50K is likely a benign variant (Mills et al., 2005). However, E50K was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E50K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the clinical and molecular information available at this time suggests that this variant is likely non-pathogenic; however, the possibility that it is a disease-associated mutation cannot be excluded. The variant is found in EPILEPSY panel(s). (less)
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Uncertain significance
(Feb 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Pyridoxal phosphate-responsive seizures
Affected status: yes
Allele origin:
germline
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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984491.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Uncertain significance
(Jun 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002555729.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: PNPO c.148G>A (p.Glu50Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: PNPO c.148G>A (p.Glu50Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251436 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in PNPO causing Pyridoxal 5'-Phosphate-Dependent Epilepsy (8.7e-05 vs 0.0011), allowing no conclusion about variant significance. c.148G>A has been reported in the literature in individuals affected with Pyridoxal 5'-Phosphate-Dependent Epilepsy (example, Mills_2005, Mills_2014, Xue_2017). However, in most cases it has been observed in cis with a splice site variant determined to be enzymatically null in functional studies (Mills_2005). Therefore these reports do not provide unequivocal conclusions about association of the variant with Pyridoxal 5'-Phosphate-Dependent Epilepsy. Experimental studies evaluating an impact on protein function have reported that the E50K variant has only mildly altered catalytic properties and the most pronounced variant effect results in a 25% decrease in normal activity (Mills_2014, Barile_2021). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pyridoxal phosphate-responsive seizures
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001206626.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 50 of the PNPO protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 50 of the PNPO protein (p.Glu50Lys). This variant is present in population databases (rs549477447, gnomAD 0.06%). This missense change has been observed in individual(s) with neonatal epileptic encephalopathy (PMID: 15772097, 24645144, 28349276). ClinVar contains an entry for this variant (Variation ID: 206440). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect PNPO function (PMID: 34769443). 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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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Pyridoxal phosphate-responsive seizures
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048213.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.148G>A (p.Glu50Lys) in PNPO gene has been submitted to ClinVar as a Variant of Uncertain Significance (VUS). The c.148G>A (p.Glu50Lys) variant is … (more)
The missense variant c.148G>A (p.Glu50Lys) in PNPO gene has been submitted to ClinVar as a Variant of Uncertain Significance (VUS). The c.148G>A (p.Glu50Lys) variant is reported with the allele frequency (0.008%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Glu at position 50 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Glu50Lys in PNPO is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant has been observed in several individuals affected with neonatal epileptic encephalopathy. However in at least 2 individuals this variant was observed to be in cis with a pathogenic variant and was not thought to contribute to the disease phenotype (Xue et al., 2017; Mills et al., 2005). This variant has been reported to have conflicting or insufficient data to determine the effect on PNPO protein function ( Mills et al., 2005). For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). (less)
Clinical Features:
Global developmental delay (present) , Seizure (present) , Attention deficit hyperactivity disorder (present)
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Uncertain significance
(Aug 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pyridoxal phosphate-responsive seizures
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003813682.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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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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Characterization of Novel Pathogenic Variants Causing Pyridox(am)ine 5'-Phosphate Oxidase-Dependent Epilepsy. | Barile A | International journal of molecular sciences | 2021 | PMID: 34769443 |
Novel phenotypes of pyridox(am)ine-5'-phosphate oxidase deficiency and high prevalence of c.445_448del mutation in Chinese patients. | Xue J | Metabolic brain disease | 2017 | PMID: 28349276 |
Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. | Mills PB | Brain : a journal of neurology | 2014 | PMID: 24645144 |
Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase. | Mills PB | Human molecular genetics | 2005 | PMID: 15772097 |
Text-mined citations for rs549477447 ...
HelpRecord last updated Apr 06, 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.