Submissions for variant NM_014141.6(CNTNAP2):c.1480G>A (p.Glu494Lys)

gnomAD frequency: 0.00017  dbSNP: rs149032771

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001721191	SCV000240766	likely benign	not provided	2021-06-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Illumina Laboratory Services, Illumina	RCV000262722	SCV000467239	uncertain significance	Pitt-Hopkins-like syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000300962	SCV000467240	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000300962	SCV000645080	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 494 of the CNTNAP2 protein (p.Glu494Lys). This variant is present in population databases (rs149032771, gnomAD 0.07%). 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: 205245). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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	RCV000715807	SCV000846638	uncertain significance	History of neurodevelopmental disorder	2016-05-09	criteria provided, single submitter	clinical testing	The p.E494K variant (also known as c.1480G>A), located in coding exon 9 of the CNTNAP2 gene, results from a G to A substitution at nucleotide position 1480. The glutamic acid at codon 494 is replaced by lysine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs149032771. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.57% (1/176) Yoruba alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (2/13006) total alleles studied, having been observed in 0.05% (2/4406) African American alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silicoanalyses, respectively.Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003967469	SCV004782300	uncertain significance	CNTNAP2-related disorder	2023-11-10	no assertion criteria provided	clinical testing	The CNTNAP2 c.1480G>A variant is predicted to result in the amino acid substitution p.Glu494Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.069% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-146997364-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.