Submissions for variant NM_007254.4(PNKP):c.992G>A (p.Trp331Ter)

gnomAD frequency: 0.00001  dbSNP: rs772727116

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188442	SCV000242056	pathogenic	not provided	2013-05-09	criteria provided, single submitter	clinical testing	The Trp331Stop nonsense mutation in the PNKP gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been reported previously to our knowledge, other loss-of-function mutations have been reported in the PNKP gene. Therefore, Trp331Stop is considered a disease-causing mutation. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857632	SCV002167375	pathogenic	Developmental and epileptic encephalopathy, 12	2022-07-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 206398). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Trp331*) in the PNKP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PNKP are known to be pathogenic (PMID: 20118933, 25728773).