Submissions for variant NM_018129.4(PNPO):c.283C>T (p.Arg95Cys)

dbSNP: rs1483600034

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001724755	SCV001950034	likely pathogenic	Pyridoxal phosphate-responsive seizures	2021-04-28	criteria provided, single submitter	clinical testing	This variant was identified as homozygous.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001724755	SCV002113821	pathogenic	Pyridoxal phosphate-responsive seizures	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 95 of the PNPO protein (p.Arg95Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with PNPO-related conditions (PMID: 17216302, 18296573). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1297019). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PNPO function (PMID: 27419045). This variant disrupts the p.Arg95 amino acid residue in PNPO. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18485777, 24645144). 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.