VCV000223153.46 - ClinVar

NM_018129.4(PNPO):c.674G>A (p.Arg225His)

Germline

Classification

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)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_018129.4(PNPO):c.674G>A (p.Arg225His)

Variation ID: 223153 Accession: VCV000223153.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.32 17: 47946670 (GRCh38) [ NCBI UCSC ] 17: 46024036 (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	Mar 6, 2016	Oct 20, 2024	Aug 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_018129.4:c.674G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060599.1:p.Arg225His	missense
NC_000017.11:g.47946670G>A
NC_000017.10:g.46024036G>A
NG_008744.1:g.10148G>A

Protein change

R225H

Other names

Canonical SPDI

NC_000017.11:47946669:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA354181 OMIM: 603287.0005 VarSome

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
Gene	OMIM	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	375	386

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.
Pyridoxal phosphate-responsive seizures	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 16, 2023	RCV000208779.16
Fetal growth restriction Growth delay Seizure	Pathogenic (1)	no assertion criteria provided	Jan 27, 2016	RCV000414812.3
Neuronopathy, distal hereditary motor, type 5A	Pathogenic (1)	criteria provided, single submitter	Oct 8, 2018	RCV000825022.3
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 1, 2022	RCV001090956.23

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 (Oct 08, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuronopathy, distal hereditary motor, type 5A Affected status: yes Allele origin: inherited	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000966216.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019
Pathogenic (Jul 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pyridoxal phosphate-responsive seizures Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429012.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Number of individuals with the variant: 2
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pyridoxal phosphate-responsive seizures Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001370445.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. This variant was detected in homozygous state.
Pathogenic (Aug 01, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001790370.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: Published functional studies have shown that R225H significantly reduces expression of PNPO activity (Mills et al., 2014; Levtova et al., 2015); Not observed at a … (more) Published functional studies have shown that R225H significantly reduces expression of PNPO activity (Mills et al., 2014; Levtova et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 31623504, 31397616, 29286531, 28832562, 29453417, 27864847, 24645144, 26535729, 25601884, 24781210, 27342130, 26938784, 24658933, 25762494, 24266778) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pyridoxal phosphate-responsive seizures (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001164129.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (2) PubMed: 24645144‚ 24658933
Pathogenic (Nov 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pyridoxal phosphate-responsive seizures Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002802817.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Aug 16, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Pyridoxal phosphate-responsive seizures Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000644981.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 24266778‚ 24645144‚ 24658933‚ 24781210‚ 25762494 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 225 of the PNPO protein (p.Arg225His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 225 of the PNPO protein (p.Arg225His). This variant is present in population databases (rs550423482, gnomAD 0.007%). This missense change has been observed in individual(s) with pyridoxine-responsive epilepsy or neonatal onset epilepsy (PMID: 24266778, 24645144, 24658933, 24781210, 25762494). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 223153). 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. Experimental studies have shown that this missense change affects PNPO function (PMID: 24645144, 24658933). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197221.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jun 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246750.24 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: PNPO: PM3:Strong, PM1, PM2, PS3:Moderate Number of individuals with the variant: 2
Pathogenic (Jan 27, 2016)	no assertion criteria provided Method: clinical testing	Growth delay Fetal growth restriction Seizure Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492675.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Feb 09, 2022)	no assertion criteria provided Method: literature only	PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000264658.2 First in ClinVar: Mar 06, 2016 Last updated: Apr 23, 2022	Publications: Plecko, B., Paul, K., Mills, P., (more...) Plecko, B., Paul, K., Mills, P., Clayton, P., Paschke, E., Maier, O., Hasselmann, O., Schmiedel, G., Kanz, S., Connolly, M., Wolf, N., Struys, E., Stockler, S., Abela, L., Hofer, D. Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology 82: 1425-1433, 2014. Ware, T. L., Earl, J., Salomons, G. (more...) Ware, T. L., Earl, J., Salomons, G. S., Struys, E. A., Peters, H. L., Howell, K. B., Pitt, J. J., Freeman, J. L. Typical and atypical phenotypes of PNPO deficiency with elevated CSF and plasma pyridoxamine on treatment. Dev. Med. Child Neurol. 56: 498-502, 2014. Comment on evidence: In 8 patients from 6 unrelated families with pyridoxamine 5-prime-phosphate oxidase deficiency (PNPOD; 610090), Plecko et al. (2014) identified a homozygous c.674G-A transition (c.674G-A, NM_001182.3) … (more) In 8 patients from 6 unrelated families with pyridoxamine 5-prime-phosphate oxidase deficiency (PNPOD; 610090), Plecko et al. (2014) identified a homozygous c.674G-A transition (c.674G-A, NM_001182.3) in exon 7 of the PNPO gene, resulting in an arg225-to-his (R225H) substitution at a conserved region in the PLP binding site. The mutation, which segregated with the disorder in the families, was not found in 100 control alleles. In vitro functional expression studies in CHO cells showed that the R225H mutant protein had no detectable enzyme activity. Most of the patients had a partial or even complete response to pyridoxine treatment. The 6 families derived from the former Yugoslavia. In a 7-year-old Greek boy with PNPOD, Ware et al. (2014) identified a homozygous R225 substitution in the PNPO gene. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed. The patient showed an initial response to treatment with pyridoxine, and later showed a sustained therapeutic response to monotherapy with high-dose pyridoxal 5-prime phosphate (PLP). Ware et al. (2014) hypothesized that some degree of pyridoxine 5-prime-phosphate binding was preserved in the mutant protein, resulting in pyridoxine responsiveness. (less)
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Comment:

Published functional studies have shown that R225H significantly reduces expression of PNPO activity (Mills et al., 2014; Levtova et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 31623504, 31397616, 29286531, 28832562, 29453417, 27864847, 24645144, 26535729, 25601884, 24781210, 27342130, 26938784, 24658933, 25762494, 24266778)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 225 of the PNPO protein (p.Arg225His). This variant is present in population databases (rs550423482, gnomAD 0.007%). This missense change has been observed in individual(s) with pyridoxine-responsive epilepsy or neonatal onset epilepsy (PMID: 24266778, 24645144, 24658933, 24781210, 25762494). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 223153). 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. Experimental studies have shown that this missense change affects PNPO function (PMID: 24645144, 24658933). For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Normal Cerebrospinal Fluid Pyridoxal 5'-Phosphate Level in a PNPO-Deficient Patient with Neonatal-Onset Epileptic Encephalopathy.	Levtova A	JIMD reports	2015	PMID: 25762494
The genetic landscape of infantile spasms.	Michaud JL	Human molecular genetics	2014	PMID: 24781210
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

Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_018129.4(PNPO):c.674G>A (p.Arg225His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...