Submissions for variant NM_014141.6(CNTNAP2):c.1105G>T (p.Val369Leu)

gnomAD frequency: 0.00003  dbSNP: rs368057493

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485828	SCV000569210	uncertain significance	not provided	2017-11-16	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CNTNAP2 gene. The V369L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant isobserved in 3/126596 (0.002%) alleles from individuals of European background, in large population cohorts (Lek et al., 2016). The V369L variant is a conservative amino acid substitution, which is not likely to impact secondaryprotein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644708	SCV000766411	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 369 of the CNTNAP2 protein (p.Val369Leu). This variant is present in population databases (rs368057493, gnomAD 0.002%). This missense change has been observed in individual(s) with speech impairment (PMID: 28440294). ClinVar contains an entry for this variant (Variation ID: 420390). 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	RCV002313248	SCV000847611	uncertain significance	Inborn genetic diseases	2016-08-19	criteria provided, single submitter	clinical testing	The p.V369L variant (also known as c.1105G>T), located in coding exon 8 of the CNTNAP2 gene, results from a G to T substitution at nucleotide position 1105. The valine at codon 369 is replaced by leucine, an amino acid with highly similar properties. This alteration was detected in an individual with significant language impairment (SLI) and normal nonverbal cognition. Of note, this individual also carried the c.701T>C alteration in the ROBO1 gene; the phase of these two alterations was not determined (Chen, et al. bioRxiv 2016 June) This variant was previously reported in the SNPDatabase as rs368057493. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied and 0.01% (1/8600) European American alleles. 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.
Illumina Laboratory Services, Illumina	RCV000644708	SCV001326006	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.