Submissions for variant NM_007254.4(PNKP):c.1074_1085del (p.Arg358_Leu361del)

dbSNP: rs796052865

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188482	SCV000242096	uncertain significance	not specified	2014-10-29	criteria provided, single submitter	clinical testing	A variant of unknown significance has been identified in the PNKP gene. The c.1074_1085delGGCCCTCCTGAG variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1074_1085delGGCCCTCCTGAG variant results in an in-frame deletion of four amino acid residues, denoted p.R358_L361del, and is not expected to result in protein truncation or nonsense-mediated mRNA decay. This deletion occurs at a position that is not conserved across species, and in-frame deletions have not been reported in the PNKP gene in association with PNKP-related disorders. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in RETT-EPI panel(s).
Invitae	RCV000576275	SCV000677003	uncertain significance	Developmental and epileptic encephalopathy, 12	2022-07-09	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 206434). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1074_1085del, results in the deletion of 4 amino acid(s) of the PNKP protein (p.Arg358_Leu361del), but otherwise preserves the integrity of the reading frame.