Submissions for variant NM_018129.4(PNPO):c.500T>C (p.Ile167Thr)

gnomAD frequency: 0.00006  dbSNP: rs546737191

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV004812302	SCV000171080	uncertain significance	not provided	2024-10-29	criteria provided, single submitter	clinical testing	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: 36539902, 33087887)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644625	SCV000766327	likely pathogenic	Pyridoxal phosphate-responsive seizures	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 167 of the PNPO protein (p.Ile167Thr). This variant is present in population databases (rs546737191, gnomAD 0.09%). This missense change has been observed in individual(s) with PNPO-related conditions (PMID: 33087887). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 138731). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PNPO protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002336278	SCV002644542	uncertain significance	Inborn genetic diseases	2018-07-10	criteria provided, single submitter	clinical testing	The p.I167T variant (also known as c.500T>C), located in coding exon 5 of the PNPO gene, results from a T to C substitution at nucleotide position 500. The isoleucine at codon 167 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000644625	SCV003923126	likely pathogenic	Pyridoxal phosphate-responsive seizures	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: PNPO c.500T>C (p.Ile167Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251324 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in PNPO causing Pyridoxal 5'-Phosphate-Dependent Epilepsy (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.500T>C has been reported in the literature in two homozygous siblings affected with Pyridoxal 5'-Phosphate-Dependent Epilepsy, with evidence of pyridoxine treatment response (Shen_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000644625	SCV005644219	likely pathogenic	Pyridoxal phosphate-responsive seizures	2024-05-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532528	SCV004727575	uncertain significance	PNPO-related disorder	2023-10-28	no assertion criteria provided	clinical testing	The PNPO c.500T>C variant is predicted to result in the amino acid substitution p.Ile167Thr. This variant has been reported in the homozygous state in siblings with epileptic encephalopathy (Family 4, Table 1, Shen et al. 2021. PubMed ID: 33087887). This variant is reported in 0.088% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-46023309-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.