Submissions for variant NM_007254.4(PNKP):c.1386+49_1387-33del

dbSNP: rs752902474

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000194165	SCV000248541	pathogenic	Microcephaly, seizures, and developmental delay	2013-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000798839	SCV000938474	pathogenic	Developmental and epileptic encephalopathy, 12	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change falls in intron 15 of the PNKP gene. It does not directly change the encoded amino acid sequence of the PNKP protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs752902474, gnomAD 0.04%). This variant has been observed in individual(s) with PNKP-related microcephaly and seizures (PMID: 20118933). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as g.5646_5662del and exon15fs4X. ClinVar contains an entry for this variant (Variation ID: 211919). Studies have shown that this variant results in skipping of exon 15 and introduces a premature termination codon (PMID: 20118933, 22508754). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001815244	SCV002063804	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335190	SCV004046229	pathogenic	PNKP-related disorders		criteria provided, single submitter	clinical testing	This intron 15 variant has been previously reported as compound heterozygous change in individuals with features of microcephaly, seizures, and developmental delay (MCSZ) (MIM: #613402; PMID: 32980744, 20118933). Experimental studies have shown that this variant disrupts mRNA splicing and causes skipping of exon 15, decreases DNA kinase activity, and results in reduced rates of DNA strand break repair (PMID: 20118933, 22508754). The c.1386+49_1387-33del variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.008% (15/182634) and is absent in the homozygous state; thus it is presumed to be rare. Based on the available evidence, the c.1386+49_1387-33del variant is classified as Pathogenic.
OMIM	RCV000194165	SCV000025299	pathogenic	Microcephaly, seizures, and developmental delay	2010-03-01	no assertion criteria provided	literature only
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000194165	SCV002098064	pathogenic	Microcephaly, seizures, and developmental delay		no assertion criteria provided	clinical testing