Submissions for variant NM_014141.6(CNTNAP2):c.2242G>T (p.Asp748Tyr)

gnomAD frequency: 0.00016  dbSNP: rs371691712

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724077	SCV000226131	uncertain significance	not provided	2018-04-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000724077	SCV000240786	uncertain significance	not provided	2021-02-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000468497	SCV000553436	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 748 of the CNTNAP2 protein (p.Asp748Tyr). This variant is present in population databases (rs371691712, gnomAD 0.1%). 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: 194401). 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 disruptive. 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.
Genetic Services Laboratory, University of Chicago	RCV000187205	SCV000594182	uncertain significance	not specified	2016-06-24	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000767938	SCV000898623	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2022-09-15	criteria provided, single submitter	clinical testing	CNTNAP2 NM_014141.5 exon 14 p.Asp748Tyr (c.2242G>T): This variant has not been reported in the literature but is present in 0.1% (22/18746) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs371691712). This variant is present in ClinVar (Variation ID:194401). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000468497	SCV001326085	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002426831	SCV002731005	uncertain significance	Inborn genetic diseases	2018-04-09	criteria provided, single submitter	clinical testing	The p.D748Y variant (also known as c.2242G>T), located in coding exon 14 of the CNTNAP2 gene, results from a G to T substitution at nucleotide position 2242. The aspartic acid at codon 748 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.