Submissions for variant NM_018129.4(PNPO):c.98A>T (p.Asp33Val)

gnomAD frequency: 0.00013  dbSNP: rs370243877

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188506	SCV000242120	pathogenic	not provided	2021-12-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced enzyme activity (Mills et al., 2014); 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: 26303608, 21292558, 23419474, 20370816, 17216302, 26821542, 27781031, 25762494, 24645144, 25256445, 34313030, Chi2021[functionalstudy], 32888189, 33981986, 34769443)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697945	SCV000826579	pathogenic	Pyridoxal phosphate-responsive seizures	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 33 of the PNPO protein (p.Asp33Val). This variant is present in population databases (rs370243877, gnomAD 0.02%). This missense change has been observed in individual(s) with pyridoxal 5'-phosphate-dependent epilepsy or neonatal onset epilepsy (PMID: 20370816, 23419474, 24645144, 25256445, 27781031). ClinVar contains an entry for this variant (Variation ID: 206458). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PNPO function (PMID: 24645144). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000697945	SCV000914773	pathogenic	Pyridoxal phosphate-responsive seizures	2017-08-25	criteria provided, single submitter	clinical testing	The PNPO c.98A>T (p.Asp33Val) variant has been reported in four studies and is found in a total of eight patients including three in a homozygous state and five in a compound heterozygous state (Schmitt et al. 2010; Goyal et al. 2013; Mills et al. 2014; Moller et al. 2016). All individuals with the p.Asp33Val variant were identified as having pyridoxamine 5-prime-phosphate oxidase (PNPO) deficiency, and one patient was also diagnosed with West syndrome (Moller et al. 2016). One of the compound heterozygous individuals carried a complex allele, however the third variant was determined to be a polymophism (Mills et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.000451 in the European (non-Finnish) population of the Exome Aggregation Consortium. When expressed in HeLa cells, the p.Asp33Val variant protein exhibited a 55% reduction in PNPO activity compared to wildtype (Mills et al. 2004). Based on the evidence, the p.Asp33Val variant is classified as pathogenic for pyridoxamine 5-prime-phosphate oxidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genetic Services Laboratory, University of Chicago	RCV000188506	SCV002072061	pathogenic	not provided	2017-07-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000697945	SCV002500308	pathogenic	Pyridoxal phosphate-responsive seizures	2022-03-10	criteria provided, single submitter	clinical testing	Variant summary: PNPO c.98A>T (p.Asp33Val) results in a non-conservative amino acid change in 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 0.00011 in 178538 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PNPO causing Pyridoxal 5'-Phosphate-Dependent Epilepsy (0.00011 vs 0.0011), allowing no conclusion about variant significance. c.98A>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with and/or undergoing genetic evaluation for pyridoxine phosphate oxidase deficiency (PNPO) and/or epilepsy (example, Schmitt_2010, Goyal_2013, Sudarsanam_2014, Mills_2014, Moller_2016). 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 (example, Mills_2014). The most pronounced variant effect results in 44% of normal PNPO activity. 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.
Ambry Genetics	RCV002381636	SCV002691286	pathogenic	Inborn genetic diseases	2017-06-28	criteria provided, single submitter	clinical testing	The p.D33V pathogenic mutation (also known as c.98A>T), located in coding exon 1 of the PNPO gene, results from an A to T substitution at nucleotide position 98. The aspartic acid at codon 33 is replaced by valine, an amino acid with highly dissimilar properties. This alteration was first reported in an individual with pyridoxine phosphate oxidase deficiency (PPOD), who also had c.246delT in the PTNO gene (Hoffmann GF et al. J. Inherit. Metab. Dis., 2007 Feb;30:96-9; Schmitt B et al. Dev Med Child Neurol, 2010 Jul;52:e133-42). In addition, this alteration has also been identified in several individuals with low pyridoxal 5'-phosphate and epilepsy, in either the homozygous or compound heterozygous state (Goyal M et al. Pediatr. Neurol., 2013 Mar;48:227-31; Mills PB et al. Brain, 2014 May;137:1350-60; Møller RS et al. Mol Syndromol, 2016 Sep;7:210-219). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000697945	SCV005400620	pathogenic	Pyridoxal phosphate-responsive seizures	2024-10-09	criteria provided, single submitter	clinical testing	Updated: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pyridoxamine 5'-phosphate oxidase deficiency (MIM#610090). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in ClinVar and in multiple unrelated individuals with pyridoxine phosphate oxidase deficiency (PNPO; PMIDs: 20370816, 23419474, 24645144, 27781031). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000697945	SCV005644213	pathogenic	Pyridoxal phosphate-responsive seizures	2024-04-11	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000697945	SCV002075240	not provided	Pyridoxal phosphate-responsive seizures		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 06-02-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.