Submissions for variant NM_007254.4(PNKP):c.1412A>T (p.His471Leu)

gnomAD frequency: 0.00015  dbSNP: rs142032281

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188460	SCV000242074	uncertain significance	not provided	2018-05-31	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the PNKP gene. The H471L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The H471L variant is observed in 10/30782 (0.03%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). The H471L variant 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000687022	SCV000814572	uncertain significance	Developmental and epileptic encephalopathy, 12	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 471 of the PNKP protein (p.His471Leu). This variant is present in population databases (rs142032281, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. ClinVar contains an entry for this variant (Variation ID: 206416). 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 PNKP protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002390494	SCV002699681	uncertain significance	Inborn genetic diseases	2017-12-16	criteria provided, single submitter	clinical testing	The p.H471L variant (also known as c.1412A>T), located in coding exon 15 of the PNKP gene, results from an A to T substitution at nucleotide position 1412. The histidine at codon 471 is replaced by leucine, 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000188460	SCV004236199	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing