Submissions for variant NM_014141.6(CNTNAP2):c.3758T>C (p.Ile1253Thr)

gnomAD frequency: 0.00033  dbSNP: rs767821521

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766802	SCV000240852	uncertain significance	not provided	2021-02-08	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18179895, 22365836, 23714751, 22872700)
Genetic Services Laboratory, University of Chicago	RCV000187270	SCV000247067	uncertain significance	not specified	2014-09-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515288	SCV000611465	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644724	SCV000766427	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1253 of the CNTNAP2 protein (p.Ile1253Thr). This variant is present in population databases (rs767821521, gnomAD 0.1%). This missense change has been observed in individual(s) with autism spectrum disorders and/or clinical features of Pitt-Hopkins-like syndrome (PMID: 18179895; Invitae). ClinVar contains an entry for this variant (Variation ID: 205319). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect CNTNAP2 function (PMID: 22872700). 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.
Ambry Genetics	RCV002314712	SCV000848133	likely benign	Inborn genetic diseases	2022-10-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Athena Diagnostics	RCV000766802	SCV001143649	likely benign	not provided	2019-01-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000644724	SCV001519896	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2019-08-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000187270	SCV005185233	likely benign	not specified	2024-05-20	criteria provided, single submitter	clinical testing	Variant summary: CNTNAP2 c.3758T>C (p.Ile1253Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251416 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database. c.3758T>C has been reported in the literature in individuals affected with Autism but has not segregated with disease (Bakkaloglu_2008) . These report(s) do not provide unequivocal conclusions about association of the variant with Autism, Susceptibility To, 15. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 18179895). ClinVar contains an entry for this variant (Variation ID: 205319). Based on the evidence outlined above, the variant was classified as likely benign.
GenomeConnect, ClinGen	RCV000644724	SCV001423449	not provided	Cortical dysplasia-focal epilepsy syndrome		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 09-25-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect - Brain Gene Registry	RCV000644724	SCV003931175	not provided	Cortical dysplasia-focal epilepsy syndrome		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 07-29-2020 by Invitae. 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/.