Submissions for variant NM_014141.6(CNTNAP2):c.2186C>T (p.Ala729Val)

gnomAD frequency: 0.00005  dbSNP: rs758221358

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480626	SCV000569372	uncertain significance	not provided	2016-03-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CNTNAP2 gene. The A729V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. However, the A729V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000813550	SCV000953914	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 729 of the CNTNAP2 protein (p.Ala729Val). This variant is present in population databases (rs758221358, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CNTNAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420509). 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. 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	RCV002431402	SCV002728544	uncertain significance	Inborn genetic diseases	2017-06-27	criteria provided, single submitter	clinical testing	The p.A729V variant (also known as c.2186C>T), located in coding exon 14 of the CNTNAP2 gene, results from a C to T substitution at nucleotide position 2186. The alanine at codon 729 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003962339	SCV004776513	uncertain significance	CNTNAP2-related condition	2023-10-26	criteria provided, single submitter	clinical testing	The CNTNAP2 c.2186C>T variant is predicted to result in the amino acid substitution p.Ala729Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-147600744-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GenomeConnect - Invitae Patient Insights Network	RCV000813550	SCV001749331	not provided	Cortical dysplasia-focal epilepsy syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-16-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.