Submissions for variant NM_014141.6(CNTNAP2):c.3179C>T (p.Ala1060Val)

gnomAD frequency: 0.00006  dbSNP: rs369254596

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766801	SCV000240809	uncertain significance	not provided	2021-08-06	criteria provided, single submitter	clinical testing	Identified in an individual with persistent developmental stuttering; however, additional information regarding the phenotype of the individual and information about parental testing were not provided and the authors concluded that CNTNAP2 variants were not associated with stuttering (Han et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24807205, 19896112)
Athena Diagnostics Inc	RCV000187227	SCV000612859	uncertain significance	not specified	2017-03-29	criteria provided, single submitter	clinical testing
Invitae	RCV000702358	SCV000831210	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-10-31	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 1060 of the CNTNAP2 protein (p.Ala1060Val). This variant is present in population databases (rs369254596, gnomAD 0.006%). This missense change has been observed in individual(s) with persistent developmental stuttering (PMID: 24807205). ClinVar contains an entry for this variant (Variation ID: 205282). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV002317087	SCV000850169	uncertain significance	Inborn genetic diseases	2020-08-10	criteria provided, single submitter	clinical testing	The p.A1060V variant (also known as c.3179C>T), located in coding exon 19 of the CNTNAP2 gene, results from a C to T substitution at nucleotide position 3179. The alanine at codon 1060 is replaced by valine, an amino acid with similar properties. This amino acid position is well 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.
Fulgent Genetics, Fulgent Genetics	RCV000765938	SCV000897358	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2018-10-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003977494	SCV004790115	uncertain significance	CNTNAP2-related condition	2023-12-07	criteria provided, single submitter	clinical testing	The CNTNAP2 c.3179C>T variant is predicted to result in the amino acid substitution p.Ala1060Val. This variant has been reported in an individual with persistent developmental stuttering ( Han TU et al 2014. PubMed ID: 24807205). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.