Submissions for variant NM_007254.4(PNKP):c.1317_1321dup (p.Ala441fs)

dbSNP: rs796052862

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000188475	SCV000226311	pathogenic	not provided	2014-11-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000188475	SCV000242089	pathogenic	not provided	2016-09-30	criteria provided, single submitter	clinical testing	The c.1317_1321dupAGCCG mutation in the PNKP gene causes a frameshift starting with codon Alanine 441, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 28 of the new reading frame, denoted p.Ala441GlufsX28. This mutation is predicted to cause loss of normal protein function through protein truncation, as the last 81 amino acids of the PNKP protein are lost and replaced with 27 incorrect amino acids. Although this mutation has not been previously reported to our knowledge, it is considered a disease-causing mutation.
Invitae	RCV001387495	SCV001588142	pathogenic	Developmental and epileptic encephalopathy, 12	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala441Glufs*28) in the PNKP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acid(s) of the PNKP protein. This variant is present in population databases (rs796052862, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with epilepsy and/or a neurodevelopmental disease (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 206429). This variant disrupts a region of the PNKP protein in which other variant(s) (p.Gln517*) have been determined to be pathogenic (PMID: 30039206). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001814094	SCV002061381	likely pathogenic	Charcot-Marie-Tooth disease type 2B2	2021-04-12	criteria provided, single submitter	clinical testing	PVS1, PM2
Ambry Genetics	RCV003243012	SCV003951333	pathogenic	Inborn genetic diseases	2023-03-22	criteria provided, single submitter	clinical testing	The c.1317_1321dupAGCCG (p.A441Efs*28) alteration, located in exon 15 (coding exon 14) of the PNKP gene, consists of a duplication of AGCCG at position 1317, causing a translational frameshift with a predicted alternate stop codon after 28 amino acids. This alteration occurs at the 3' terminus of the PNKP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 15% of the protein. Premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in conjunction with another variant in PNKP in an individual with clinical features of PNKP-related neurodevelopmental disorder (Bras, 2015). Based on internal structural analysis, p.A441Efs*28 is deleterious. This variant is destabilizing to the local structure and disrupts a significant portion of a domain (Jilani, 1999; Karimi-Busheri, 1999; Koch, 2004; Mani, 2010; Aceytuno, 2017). Based on the available evidence, this alteration is classified as pathogenic.