Submissions for variant NM_007254.4(PNKP):c.636+1G>T

gnomAD frequency: 0.00004  dbSNP: rs1247055716

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502084	SCV000596489	pathogenic	Microcephaly, seizures, and developmental delay	2017-04-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001328605	SCV001519759	likely pathogenic	Charcot-Marie-Tooth disease type 2B2	2020-09-04	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376960	SCV001574168	likely pathogenic	Developmental and epileptic encephalopathy, 12	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 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 (no rsID available, gnomAD 0.007%). 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: 436354). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480656	SCV004225283	likely pathogenic	not provided	2023-04-11	criteria provided, single submitter	clinical testing	PM2, PVS1
PreventionGenetics, part of Exact Sciences	RCV004535608	SCV004710505	likely pathogenic	PNKP-related disorder	2023-12-06	no assertion criteria provided	clinical testing	The PNKP c.636+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in PNKP are expected to be pathogenic. This variant is interpreted as likely pathogenic.