17-47945943-T-C

Variant names:

• chr17-47945943-T-C
• rs546737191
• NM_018129.4:c.500T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP5 BS1_Supporting

The NM_018129.4(PNPO):​c.500T>C​(p.Ile167Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PNPO NM_018129.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 7.77
• Publications: 4 publications found

Genes affected

PNPO (HGNC:30260): (pyridoxamine 5'-phosphate oxidase) The enzyme encoded by this gene catalyzes the terminal, rate-limiting step in the synthesis of pyridoxal 5'-phosphate, also known as vitamin B6. Vitamin B6 is a required co-factor for enzymes involved in both homocysteine metabolism and synthesis of neurotransmitters such as catecholamine. Mutations in this gene result in pyridoxamine 5'-phosphate oxidase (PNPO) deficiency, a form of neonatal epileptic encephalopathy. [provided by RefSeq, Oct 2008]

PNPO Gene-Disease associations (from GenCC):

• pyridoxal phosphate-responsive seizures

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000263798 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_018129.4
• PP5: Variant 17-47945943-T-C is Pathogenic according to our data. Variant chr17-47945943-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138731.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000114 (166/1461734) while in subpopulation SAS AF = 0.000707 (61/86256). AF 95% confidence interval is 0.000564. There are 0 homozygotes in GnomAdExome4. There are 97 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018129.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	NM_018129.4	MANE Select	c.500T>C	p.Ile167Thr	missense	Exon 5 of 7	NP_060599.1
	PNPO	NM_001436305.1		c.417+331T>C		intron	N/A	NP_001423234.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPO	ENST00000642017.2	MANE Select	c.500T>C	p.Ile167Thr	missense	Exon 5 of 7	ENSP00000493302.2
	PNPO	ENST00000225573.5	TSL:1	c.417+331T>C		intron	N/A	ENSP00000225573.5
	PNPO	ENST00000434554.7	TSL:2	c.446T>C	p.Ile149Thr	missense	Exon 4 of 6	ENSP00000399960.3

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 251324 AF XY: 0.000199

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1461734 Hom.: 0 Cov.: 32 AF XY: 0.000133 AC XY: 97 AN XY: 727172

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.000707 AC: 61 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53286

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.0000683 AC: 76 AN: 1112008

Other (OTH) AF: 0.000215 AC: 13 AN: 60392

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74488

African (AFR) AF: 0.0000722 AC: 3 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pyridoxal phosphate-responsive seizures Pathogenic:4

Mar 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

May 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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.

Jun 23, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Likely pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 178 heterozygote(s), 0 homozygote(s)); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from isoleucine to threonine; This variant is heterozygous; This gene is associated with autosomal recessive disease; Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 1 heterozygote(s), 0 homozygote(s)); Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as likely pathogenic and as a VUS by clinical laboratories (ClinVar). This variant has been reported in two homozygous siblings affected with early onset pyridoxal 5'-phosphate-dependent epilepsy (PMID: 33087887); Segregation evidence for this variant is inconclusive. This variant has been reported in two affected homozygous siblings, with both unaffected parents being heterozygous carriers (PMID: 33087887); No published functional evidence has been identified for this variant; No comparable missense variants have previous evidence for pathogenicity; Variant is located in the annotated pyridoxamine 5'-phosphate oxidase domain (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with pyridoxamine 5'-phosphate oxidase deficiency (MIM#610090); Variants in this gene are known to have variable expressivity (OMIM).

Inborn genetic diseases Uncertain:1

Jul 10, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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.

not provided Uncertain:1

Sep 15, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously as an apparently homozygous variant in a patient with seizures; however, no further clinical or segregation information was provided (PMID: 40336053); 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, 40336053)

PNPO-related disorder Uncertain:1

Oct 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.8
PrimateAI	Uncertain	0.70	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
MVP		0.97
ClinPred		0.36	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.73
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs546737191; hg19: chr17-46023309;