Submissions for variant NM_007254.4(PNKP):c.610C>T (p.Arg204Ter)

gnomAD frequency: 0.00001  dbSNP: rs796052850

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188430	SCV000242043	pathogenic	not provided	2014-02-12	criteria provided, single submitter	clinical testing	p.Arg204Stop (CGA>TGA): c.610 C>T in exon 6 of the PNKP gene (NM_007254.2) The Arg204Stop 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, it is considered a disease-causing mutation.The variant is found in EPILEPSY panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175506	SCV001339109	likely pathogenic	not specified	2020-03-20	criteria provided, single submitter	clinical testing	Variant summary: PNKP c.610C>T (p.Arg204X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported as disease-associated mutations in HGMD and in the literature and have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4e-06 in 251368 control chromosomes (gnomAD). To our knowledge, no occurrence of c.610C>T in individuals affected with PNKP-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation in 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005055689	SCV005717751	pathogenic	Developmental and epileptic encephalopathy, 12	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg204*) 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). This variant is present in population databases (rs796052850, gnomAD 0.004%). 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: 206388). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.