ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1009G>C (p.Glu337Gln)

gnomAD frequency: 0.00006  dbSNP: rs780121125
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001698362 SCV000534473 likely benign not provided 2019-04-03 criteria provided, single submitter clinical testing
Invitae RCV000541153 SCV000650109 uncertain significance Developmental and epileptic encephalopathy, 12 2022-08-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 337 of the PNKP protein (p.Glu337Gln). This variant is present in population databases (rs780121125, gnomAD 0.008%). This missense change has been observed in individual(s) with juvenile myoclonic epilepsy (PMID: 29924869). ClinVar contains an entry for this variant (Variation ID: 391407). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV002436347 SCV002747597 uncertain significance Inborn genetic diseases 2020-01-08 criteria provided, single submitter clinical testing The p.E337Q variant (also known as c.1009G>C), located in coding exon 10 of the PNKP gene, results from a G to C substitution at nucleotide position 1009. The glutamic acid at codon 337 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a subject with juvenile myoclonic epilepsy (Lee CG et al. PLoS ONE, 2018 Jun;13:e0199321). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other 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.

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