Submissions for variant NM_001077350.3(NPRL3):c.318+3A>T

gnomAD frequency: 0.00002  dbSNP: rs746765533

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000696091	SCV000824638	uncertain significance	Epilepsy, familial focal, with variable foci 3	2022-09-22	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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 574218). This variant has not been reported in the literature in individuals affected with NPRL3-related conditions. This variant is present in population databases (rs746765533, gnomAD 0.05%). This sequence change falls in intron 4 of the NPRL3 gene. It does not directly change the encoded amino acid sequence of the NPRL3 protein. It affects a nucleotide within the consensus splice site.
GeneDx	RCV001662765	SCV001875033	uncertain significance	not provided	2021-07-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27535533)
New York Genome Center	RCV000696091	SCV002506741	uncertain significance	Epilepsy, familial focal, with variable foci 3	2021-05-24	criteria provided, single submitter	clinical testing	The inherited heterozygous splice region variant c.318+3A>T has not been reported in the literature in individuals with NPRL3-related disease. The variant affects a nucleotide within the consensus splice site of the intron 4 and is absent in the gnomAD v3.1.1 database, indicating a rare allele. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID:17576681; PMID:9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Still, this prediction has not been confirmed by published transcriptional studies. Based on the available evidence, the inherited variant c.318+3A>T in the NPRL3 gene is classified as a variant of uncertain significance.
GenomeConnect - Brain Gene Registry	RCV000696091	SCV003930430	not provided	Epilepsy, familial focal, with variable foci 3		no assertion provided	phenotyping only	This participant was tested at multiple clinical laboratories and the variant was classified as Uncertain significance at both laboratories. Variant most recently reported on 05-24-2021 by New York Genome Center and 02-23-2021 by Sema4. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.