Submissions for variant NM_018129.4(PNPO):c.148G>A (p.Glu50Lys)

gnomAD frequency: 0.00001  dbSNP: rs549477447

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188488	SCV000242102	uncertain significance	not provided	2017-02-13	criteria provided, single submitter	clinical testing	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042917	SCV001206626	uncertain significance	Pyridoxal phosphate-responsive seizures	2022-08-22	criteria provided, single submitter	clinical testing	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.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001042917	SCV001984491	uncertain significance	Pyridoxal phosphate-responsive seizures	2020-02-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271452	SCV002555729	uncertain significance	not specified	2024-04-29	criteria provided, single submitter	clinical testing	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 estimated 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 (e.g. Mills_2005, Mills_2014, Xue_2017). However, in some cases it was observed in cis with a splice site variant determined to be enzymatically null in functional studies (Mills_2005). In a case with global developmental delay, seizures, and attention deficit hyperactivity disorder, it was found in trans with the splice site variant (Pranav Chand_2023). 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). The following publications have been ascertained in the context of this evaluation (PMID: 24645144, 34769443, 15772097, 28349276, 36801247). ClinVar contains an entry for this variant (Variation ID: 206440). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV001042917	SCV003813682	uncertain significance	Pyridoxal phosphate-responsive seizures	2019-08-21	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001042917	SCV004048213	uncertain significance	Pyridoxal phosphate-responsive seizures		criteria provided, single submitter	clinical testing	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).