Submissions for variant NM_014141.6(CNTNAP2):c.755-5C>T

gnomAD frequency: 0.00010  dbSNP: rs369675346

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000124354	SCV000167785	benign	not specified	2014-02-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago	RCV000124354	SCV000594165	likely benign	not specified	2016-06-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000711334	SCV000707726	uncertain significance	not provided	2017-04-24	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000711334	SCV000841676	uncertain significance	not provided	2018-05-22	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768190	SCV000898621	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2021-03-30	criteria provided, single submitter	clinical testing	CNTNAP2 NM_014141.5 exon 6 c.755-5C>T: This variant has not been reported in the literature but is present in 23/126370 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs369675346). This variant is present in ClinVar (Variation ID:136809). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant; splice prediction tools suggest that this variant may not affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080931	SCV001000982	likely benign	Cortical dysplasia-focal epilepsy syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390279	SCV002675197	uncertain significance	Inborn genetic diseases	2017-12-27	criteria provided, single submitter	clinical testing	The c.755-5C>T intronic variant results from a C to T substitution 5 nucleotides upstream from exon 6 in the CNTNAP2 gene. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000124354	SCV004241489	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: CNTNAP2 c.755-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00027 in 251082 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CNTNAP2 causing Pitt-Hopkins-Like Syndrome 1 (0.00027 vs 0.0011), allowing no conclusion about variant significance. c.755-5C>T has been reported in the literature in an individual affected with Rolandic epilepsy (Bobbili_2018). This report does not provide unequivocal conclusions about association of the variant with Pitt-Hopkins-Like Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29358611). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including uncertain significance (n=4), pathogenic (n=1) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Bioinformatics Core, Luxembourg Center for Systems Biomedicine	RCV000656005	SCV000588281	pathogenic	Childhood epilepsy with centrotemporal spikes	2017-01-01	no assertion criteria provided	case-control	CAADphred>15