Submissions for variant NM_014141.6(CNTNAP2):c.653C>T (p.Thr218Met)

gnomAD frequency: 0.00007  dbSNP: rs771028883

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000733910	SCV000240842	uncertain significance	not provided	2014-07-31	criteria provided, single submitter	clinical testing	p.Thr218Met (ACG>ATG): c.653 C>T in exon 5 of the CNTNAP2 gene (NM_014141.5). The T218M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T218M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI,INFANT-EPI panel(s).
Genetic Services Laboratory, University of Chicago	RCV000187260	SCV000247070	uncertain significance	not specified	2015-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314711	SCV000849269	uncertain significance	Inborn genetic diseases	2017-03-31	criteria provided, single submitter	clinical testing	The p.T218M variant (also known as c.653C>T), located in coding exon 5 of the CNTNAP2 gene, results from a C to T substitution at nucleotide position 653. The threonine at codon 218 is replaced by methionine, an amino acid with similar 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.
Eurofins Ntd Llc (ga)	RCV000733910	SCV000862015	uncertain significance	not provided	2018-06-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764697	SCV000895831	uncertain significance	Autism, susceptibility to, 15; Cortical dysplasia-focal epilepsy syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001047524	SCV001211488	uncertain significance	Cortical dysplasia-focal epilepsy syndrome	2022-04-15	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 218 of the CNTNAP2 protein (p.Thr218Met). This variant is present in population databases (rs771028883, gnomAD 0.03%). 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: 205310). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.