ClinVar Miner

Submissions for variant NM_007254.4(PNKP):c.1360C>G (p.Leu454Val)

dbSNP: rs200611702
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000809805 SCV000949981 uncertain significance Developmental and epileptic encephalopathy, 12 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 454 of the PNKP protein (p.Leu454Val). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 653942). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV001270054 SCV001448789 uncertain significance Microcephaly, seizures, and developmental delay 2019-07-08 criteria provided, single submitter clinical testing
GeneDx RCV001759560 SCV001995156 uncertain significance not provided 2019-10-30 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002537319 SCV003734289 uncertain significance Inborn genetic diseases 2022-02-11 criteria provided, single submitter clinical testing The c.1360C>G (p.L454V) alteration is located in exon 15 (coding exon 14) of the PNKP gene. This alteration results from a C to G substitution at nucleotide position 1360, causing the leucine (L) at amino acid position 454 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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