Submissions for variant NM_014141.6(CNTNAP2):c.136G>A (p.Val46Met)

gnomAD frequency: 0.00059  dbSNP: rs137924687

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724579	SCV000227423	uncertain significance	not provided	2015-03-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000724579	SCV000240744	uncertain significance	not provided	2024-12-16	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously reported as pathogenic or benign in association with neurodevelopmental disorders to our knowledge; This variant is associated with the following publications: (PMID: 29463802, 26934580, 28569743)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644725	SCV000766428	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 46 of the CNTNAP2 protein (p.Val46Met). This variant is present in population databases (rs137924687, gnomAD 0.2%). 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: 195292). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine 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	RCV002317014	SCV000851375	uncertain significance	Inborn genetic diseases	2021-01-08	criteria provided, single submitter	clinical testing	The c.136G>A (p.V46M) alteration is located in exon 2 (coding exon 2) of the CNTNAP2 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the valine (V) at amino acid position 46 to be replaced by a methionine (M). The p.V46M alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV001818422	SCV002069864	uncertain significance	not specified	2018-12-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485141	SCV002784002	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2021-08-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748628	SCV005353880	uncertain significance	CNTNAP2-related disorder	2024-04-25	no assertion criteria provided	clinical testing	The CNTNAP2 c.136G>A variant is predicted to result in the amino acid substitution p.Val46Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.