rs370243877

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PP3_ModeratePP5_Very_StrongBS1_Supporting

The NM_018129.4(PNPO):c.98A>T(p.Asp33Val) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,567,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D33D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

PNPO
NM_018129.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 4.69

Publications

9 publications found

Variant links:

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

PNPO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.877

PP5

Variant 17-47941773-A-T is Pathogenic according to our data. Variant chr17-47941773-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 206458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000232 (329/1415666) while in subpopulation NFE AF = 0.000293 (319/1087976). AF 95% confidence interval is 0.000267. There are 0 homozygotes in GnomAdExome4. There are 139 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPO	NM_018129.4 link	c.98A>T	p.Asp33Val	missense_variant	Exon 1 of 7	ENST00000642017.2	NP_060599.1
PNPO	NM_001436305.1 link	c.98A>T	p.Asp33Val	missense_variant	Exon 1 of 6		NP_001423234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPO	ENST00000642017.2 link	c.98A>T	p.Asp33Val	missense_variant	Exon 1 of 7		NM_018129.4	ENSP00000493302.2

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000106

AC:

AN:

178538

AF XY:

0.0000940

show subpopulations

Gnomad AFR exome

AF:

0.0000965

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000247

Gnomad NFE exome

AF:

0.000192

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000232

AC:

329

AN:

1415666

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

139

AN XY:

699970

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32406

American (AMR)

AF:

0.00

AC:

AN:

38432

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25320

East Asian (EAS)

AF:

0.00

AC:

AN:

37126

South Asian (SAS)

AF:

0.00

AC:

AN:

80504

European-Finnish (FIN)

AF:

0.000120

AC:

AN:

49806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5470

European-Non Finnish (NFE)

AF:

0.000293

AC:

319

AN:

1087976

Other (OTH)

AF:

0.0000682

AC:

AN:

58626

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41418

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.0000931

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyridoxal phosphate-responsive seizures

Pathogenic:5Other:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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 -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method: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. -

Mar 10, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

not provided

Pathogenic:3

Jul 11, 2017

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PNPO: PM3:Very Strong, PM2, PP3, PS3:Supporting -

Dec 09, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

Inborn genetic diseases

Pathogenic:1

Jun 28, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.9

L;L;L;.

PhyloP100

4.7

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.0

.;D;D;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

.;D;D;.

Sift4G

Uncertain

0.0080

.;D;D;.

Polyphen

0.99

D;.;.;.

Vest4

0.75, 0.88

MVP

0.92

MPC

1.6

ClinPred

0.77

GERP RS

5.2

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.74

gMVP

0.77

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over