17-47946670-G-T

Position:

• chr17-47946670-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_018129.4(PNPO):​c.674G>T​(p.Arg225Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPO NM_018129.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.64

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a binding_site (size 2) in uniprot entity PNPO_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_018129.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-47946669-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 206450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-47946670-G-T is Pathogenic according to our data. Variant chr17-47946670-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 206451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPO	NM_018129.4	c.674G>T	p.Arg225Leu	missense_variant	7/7	ENST00000642017.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPO	ENST00000642017.2	c.674G>T	p.Arg225Leu	missense_variant	7/7		NM_018129.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2016

The R225L missense variant in the PNPO gene has been reported previously as a homozygous variant in two siblings with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency (Sund et al., 2013). R225L 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 alters a highly conserved position in the predicted substrate binding region of the PNP oxidase enzyme and functional studies indicate that the R225 residue lies within a region of the protein that is necessary for substrate binding and catalysis (Musayev et al., 2009). In addition, other missense variants at the same position (R225H, R225C) have been reported previously in association with PNPO deficiency. -

Pyridoxal phosphate-responsive seizures Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 05, 2023

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 225 of the PNPO protein (p.Arg225Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 22858719, 28985901). ClinVar contains an entry for this variant (Variation ID: 206451). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNPO protein function. This variant disrupts the p.Arg225 amino acid residue in PNPO. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22858719, 24266778, 24645144, 24658933). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
Polyphen		1.0	.;D;.;.;.
MutPred		0.94		.;Loss of MoRF binding (P = 0.007);.;.;.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs550423482; hg19: chr17-46024036;