Submissions for variant NM_007254.4(PNKP):c.1295_1298+6del

dbSNP: rs587784366

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000147346	SCV000194721	pathogenic	Microcephaly, seizures, and developmental delay	2014-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000188473	SCV000242087	pathogenic	not provided	2013-09-19	criteria provided, single submitter	clinical testing	The c.1295_1298+6delCCAGGTAGCG mutation in the PNKP gene results in the deletion of ten nucleotides at the exon 14/intron 14 boundary, thereby destroying the canonical splice donor site in intron 14. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. Although this mutation has not been previously reported to our knowledge, it is considered a disease-causing mutation.The variant is found in CHILD-EPI,EPILEPSY panel(s).
Eurofins Ntd Llc (ga)	RCV000188473	SCV000700789	likely pathogenic	not provided	2016-06-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825541	SCV000966857	likely pathogenic	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	2016-12-23	criteria provided, single submitter	clinical testing	The c.1295_1298+6del (NM_007254.3 c.1295_1298+6delCCAGGTAGCG) variant in PNKP ha s not been reported in the literature. It has been identified in 2/8264 of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs587784366). This variant is predicted to alter splicing or cause a frameshift at this position. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the PNKP gene h as been associated with ataxia with oculomotor apraxia. In summary, although add itional studies are required to fully establish a null effect on the protein, th e c.1295_1298+6delCCAGGTAGCG variant in PNKP is likely pathogenic for ataxia wit h oculomotor apraxia in an autosomal recessive manner based upon its predicted f unctional impact.
Invitae	RCV001070856	SCV001236133	pathogenic	Developmental and epileptic encephalopathy, 12	2023-12-04	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 14 (c.1295_1298+6del) of the PNKP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PNKP are known to be pathogenic (PMID: 20118933, 25728773). This variant is present in population databases (rs587784366, gnomAD 0.03%). This variant has been observed in individual(s) with PNKP-related conditions (PMID: 31167812). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 159788). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PNKP function (PMID: 32504494). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000188473	SCV002019446	pathogenic	not provided	2021-04-06	criteria provided, single submitter	clinical testing